Therapeutic nucleosides

ABSTRACT

Antiviral nucleoside analogues contain a substituted benzimidazole base attached to a carbocyclic ring in place of the conventional sugar residue. Particularly preferred compounds include those in which the 2-, 5- and 6- positions of the benzimidazole base are substituted by halogen. The compounds have activity against herpes virus especially cytomegalovirus and also hepatitis B virus infections.

This application is a continuation-in-part of International PatentApplication No. PCT/GB93/00479, filed Mar. 8, 1993, now published (onSep. 16, 1993) as WO93/18009, and designating therein the United Statesof America as a Designated State. International Patent Application No.PCT/GB93/00479 is incorporated herein by reference.

The present invention relates to purine nucleoside analogues containinga carbocyclic ring in place of the sugar residue, pharmaceuticallyacceptable derivatives thereof, and their use in medical therapy,particularly for the treatment of certain viral infections.

Hepatitis B virus (HBV) is a small DNA containing virus which infectshumans. It is a member of the class of closely related viruses known asthe hepadnaviruses, each member of which selectively infects eithermammalian or avian hosts, such as the woodchuck and the duck.

Worldwide, HBV is a viral pathogen of major consequence. It is mostcommon in Asian countries, and prevalent in sub-Saharan Africa. Thevirus is etiologically associated with primary hepatocellular carcinomaand is thought to cause 80% of the world's liver cancer. In the UnitedStates more than ten thousand people are hospitalized for HBV illnesseach year, an average of 250 die with fulminant disease.

The United States currently contains an estimated pool of 500,000-1million infectious carriers. Chronic active hepatitis will develop inover 25% of carriers, and often progresses to cirrhosis. It is estimatedthat 5000 people die from HBV-related cirrhosis each year in the USA,and that perhaps 1000 die from HBV-related liver cancer. Even when auniversal HBV vaccine is in place, the need for effective anti-HBVcompounds will continue. The large reservoir of persistently infectedcarriers, estimated at 220 million worldwide, will receive no benefitfrom vaccination and will continue at high risk for HBV-induced liverdisease. This carrier population serves as the source of infection ofsusceptible individuals perpetuating the instance of diseaseparticularly in endemic areas or high risk groups such as IV drugabusers and homosexuals. Thus, there is a great need for effectiveantiviral agents, both to control the chronic infection and reduceprogression to hepatocellular carcinoma.

Clinical effects of infection with HBV range from headache, fever,malaise, nausea, vomiting, anorexia and abdominal pains. Replication ofthe virus is usually controlled by the immune response, with a course ofrecovery lasting weeks or months in humans, but infection may be moresevere leading to persistent chronic liver disease as outlined above.

In "Viral Infections of Humans" (second edition, Ed., Evans, A. S.(1982) Plenum Publishing Corporation, New York), Chapter 12 describes indetail the etiology of viral hepatitis infections.

Of the DNA viruses, the herpes group is the source of many common viralillnesses in man. The group includes cytomegalovirus (CMV), Epstein-Barrvirus (EBV), varicella zoster virus (VZV), herpes simplex virus (HSV)and human herpes virus 6 (HHV6).

In common with other herpes viruses, infection with CMV leads to alife-long association of virus and host and, following a primaryinfection, virus may be shed for a number of years. Clinical effectsrange from death and gross disease (microcephaly, hepatosplenemegaly,jaundice, mental retardation) through failure to thrive, susceptibilityto chest and ear infections to a lack of any obvious ill effect. CMVinfection in AIDS patients is a predominant cause of morbidity as, in 40to 80% of the adult population, it is present in a latent form and canbe reactivated in immunocompromised patients.

EBV causes infectious mononucleosis and is also suggested as thecausative agent of nasopharyngeal cancer, immunoblastic lymphoma,Burkitt's lymphoma and hairy leukoplakia.

VZV causes chicken pox and shingles. Chicken pox is the primary diseaseproduced in a host without immunity. In young children, it is usually amild illness characterized by a vesicular rash and fever. Shingles isthe recurrent form of the disease which occurs in adults who werepreviously infected with varicella. The clinical manifestations ofshingles include neuralgia and a vesicular skin rash that is unilateraland dermatomal in distribution. Spread of inflammation may lead toparalysis or convulsions and coma can occur if the meninges becomesaffected. In immunodeficient patients, VZV may disseminate causingserious or even fatal illness.

HSV 1 and HSV 2 are some of the most common infectious agents of man.Most of these viruses are able to persist in the host's neural cells.Once infected, individuals are at risk of recurrent clinicalmanifestation of infection which can be both physically andpsychologically distressing. HSV infection is often characterized byextensive lesions of the skin, mouth and/or genitals. Primary infectionsmay be subclinical although they tend to be more severe than infectionsin individuals previously exposed to the virus. Ocular infections by HSVcan lead to keratitis or cataracts. Infection in the newborn, inimmunocompromised patients or penetration of infection into the centralnervous system can prove fatal. HHV6 is the causative agent of roseolainfantum (exanthum subitum) in children which is characterized by feverand the appearance of a rash after the fever has declined. HHV6 has alsobeen implicated in syndromes of fever and/or rash and pneumonia orhapatitis in immunocompromised patients.

It has now been discovered that certain substituted benzimidazolecompounds as referred to below, are useful for the treatment orprophylaxis of certain viral infections. According to a first aspect ofthe present invention, novel compounds of the formulas (I) and (I-1) areprovided: ##STR1## wherein R¹ is H, CH₃ or CH₂ OH; R² is H or OH; R³ isH or OH; or R² and R³ together form a bond;

R⁴ is H, Cl, Br, I, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, C₁₋₄ perfluoroalkyl (e.g., trifluoromethyl), NH₂, C₁₋₄alkylamino, C₁₋₄ dialkylamino, C₃₋₇ cycloalkylamino, diC₃₋₇cycloalkylamino, N-C₁₋₄ alkyl-N-C₃₋₇ cycloalkylamino, N-C₁₋₄alkyl-N-C₃₋₇ cycloalkylC₁₋₄ alkylamino, diC₃₋₇ cycloalkylC₁₋₄alkylamino, C₃₋₇ cycloalkylC₁₋₄ alkylamino, N-C₃₋₇ cycloalkyl-N-C₃₋₇cycloalkylC₁₋₄ alkylamino, SH, C₁₋₄ alkylthio, C₆₋₁₀ arylC₁₋₄ alkylthio,OH, C₁₋₄ alkoxy, C₆₋₁₀ arylC₁₋₄ alkyoxy or C₆₋₁₀ arylC₁₋₄ alkyl; and R⁵,R⁶ and R⁷ are independently selected from H, F, Cl, Br, I, CF₃ and CH₃,provided that at least one of R¹, R² and R³ is or contains OH;

and pharmaceutically acceptable derivatives thereof.

Preferred compounds of formula (I) and (I-1) are those show in formula(IA) and (IA-1): ##STR2## wherein R² is H or OH. Particularly preferredcompounds of formulas (I), (I-1), (IA), and (IA-1) are those wherein R⁴is CH₃, Cl or Br; R⁵ is H; and R⁶ and R⁷ are each Cl. Most preferredcompounds of formula (I), (I-1), (IA) and (IA-1) are those wherein R⁴ iscyclopropylamino, isopropylamino or tert-butylamino; R⁵ is H; and R⁶ andR⁷ are Cl.

It is to be understood that the present invention encompasses theparticular enantiomers depicted in formula (I) and (I-1), includingtautomers of the purine, alone and in combination with theirmirror-image enantiomers. Enantiomers depicted by formula (I) arepreferred and preferably are provided substantially free of thecorresponding enantiomer to the extent that it is generally in admixturewith less than 10% w/w, preferably less than 5% w/w, more preferablyless than 2% w/w and most preferably less than 1% w/w of thecorresponding enantiomer based on the total weight of the mixture.Enantiomers depicted by formula (I-1) are most preferred and preferablyare provided substantially free of the corresponding enantiomer to theextent that it is generally in admixture with less than 10% w/w,preferably less than 5% w/w, more preferably less than 2% w/w and mostpreferably less than 1% w/w of the corresponding enantiomer based on thetotal weight of the mixture.

Particularly preferred examples of compounds of formula (I) are:

(1R, 2S, 3S,5S)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1S, 2R, 3R,5R)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopropanediol

(±)-(1R*, 2R*,4S*)-2-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-4-(hydroxymethyl)cyclopentanol;

(±)-(1R*, 2S*, 3S*,5S*)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol;

(±)-(1R*, 2S*, 3S*,5S*)-5-(2,5,6-Trichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol;

(±)-(1R*, 2S*,3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediol;and

(±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-Dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol;

and pharmaceutically acceptable salts thereof.

Most preferred compounds of formula (I) are:

(±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;

(1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;

(±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;

(1R, 2S, 3S,5S)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;and

(±)-(1R*, 2S*, 3S*,5S*)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;

and pharmaceutically acceptable salts thereof.

The compounds of formulas (I) and (I-1) above and their pharmaceuticallyacceptable derivatives are herein referred to as the compounds accordingto the invention.

In a further aspect of the invention there are provided the compoundsaccording to the invention for use in medical therapy particularly forthe treatment or prophylaxis of viral infections such as herpes viralinfections. To date compounds of the invention have been shown to beactive against hepatitis B virus (HBV) and cytomegalovirus (CMV)infections, although early results suggest that the invention could alsobe active against other herpes virus infections such as EBV, VZV, HSVIand II and HHV6.

Other viral conditions which may be treated in accordance with theinvention have been discussed in the introduction hereinbefore.

In yet a further aspect of the present invention there is provided:

a) A method for the treatment or prophylaxis of a hepadnaviral infectionsuch as hepatitis B or a herpes viral infection such as CMV whichcomprises treating the subject with a therapeutically effective amountof a compound according to the invention.

b) Use of a compound according to the invention in the manufacture of amedicament for the treatment or prophylaxis of any of theabove-mentioned infections or conditions.

By "a pharmaceutically acceptable derivative" is meant anypharmaceutically or pharmacologically acceptable salt, ester or salt ofsuch ester of a compound according to the invention, or any compoundwhich, upon administration to the recipient, is capable of providing(directly or indirectly) a compound according to the invention, or anantivirally active metabolite or residue thereof.

Preferred esters of the compounds of the invention include carboxylicacid esters in which the non-carbonyl moiety of the ester grouping isselected from straight or branched chain alkyl, e.g. n-propyl, t-butyl,n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl),aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionallysubstituted by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy or amino); sulfonateesters such as alkyl- or aralkylsulfonyl (e.g. methanesulfonyl); aminoacid esters (e.g. L-valyl or L-isoleucyl); and mono-, di- ortriphosphate esters. The phosphate esters may be further esterified by,for example, a C₁₋₂₀ alcohol or reactive derivative thereof, or by a2,3-di(C₆₋₂₄)acyl glycerol.

With regard to the above-described esters, unless otherwise specified,any alkyl moiety present advantageously contains 1 to 18 carbon atoms,particularly 3 to 6 carbon atoms such as the pentanoate. Any aryl moietypresent in such esters advantageously comprises a phenyl group.

Any reference to any of the above compounds also includes a reference toa pharmaceutically acceptable salt thereof.

Physiologically acceptable salts include salts of organic carboxylicacids such as acetic, lactic, tartaric, malic, isethionic, lactobionic,p-aminobenzoic and succinic acids; organic sulfonic acids such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids and inorganic acids such as hydrochloric, sulfuric, phosphoric andsulfamic acids.

The above compounds according to the invention and theirpharmaceutically acceptable derivatives may be employed in combinationwith other therapeutic agents for the treatment of the above infectionsor conditions. Examples of such further therapeutic agents includeagents that are effective for the treatment of viral infections orassociated conditions such as acyclic nucleosides (e.g. acyclovir),immunomodulatory agents such as thymosin, ribonucleotide reductaseinhibitors such as 2-acetylpyridine5-[(2-chloroanilino)thiocarbonyl)thiocarbonohydrazone, interferons suchas α-interferon, 1-β-D-arabinofuranosyl-5-(1-propynyl)uracil,3'-azido-3'-deoxythymidine, ribavirin and phosphonoformic acid. Thecomponent compounds of such combination therapy may be administeredsimultaneously, in either separate or combined formulations, or atdifferent times, e.g. sequentially such that a combined effect isachieved.

The compounds according to the invention, also referred to herein as theactive ingredient, may be administered for therapy by any suitable routeincluding oral, rectal, nasal, topical (including transdermal, buccaland sublingual), vaginal and parenteral (including subcutaneous,intramuscular, intravenous and intradermal). It will be appreciated thatthe preferred route will vary with the condition and age of therecipient, the nature of the infection and the chosen active ingredient.

In general a suitable dose for each of the above-mentioned conditionswill be in the range of 0.01 to 250 mg per kilogram body weight of therecipient (e.g. a human) per day, preferably in the range of 0.1 to 100mg per kilogram body weight per day and most preferably in the range 1.0to 20 mg per kilogram body weight per day. (Unless otherwise indicated,all weights of active ingredient are calculated as the parent compoundof formula (I); for salts or esters thereof, the weights would beincreased proportionally.) The desired dose is preferably presented astwo, three, four, five, six or more sub-doses administered atappropriate intervals throughout the day. These sub-doses may beadministered in unit dosage forms, for example, containing 10 to 1000mg, preferably 20 to 500 mg, and most preferably 100 to 400 mg of activeingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.025 toabout 100 μM, preferably about 0.1 to 70 μM, most preferably about 0.25to 50 μM. This may be achieved, for example, by the intravenousinjection of a 0.1 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 0.1 toabout 250 mg/kg of the active ingredient. Desirable blood levels may bemaintained by a continuous infusion to provide about 0.01 to about 5.0mg/kg/hour or by intermittent infusions containing about 0.4 to about 15mg/kg of the active ingredient.

While it is possible for the active ingredient to be administered aloneit is preferable to present it as a pharmaceutical formulation. Theformulations of the present invention comprise at least one activeingredient, as defined above, together with one or more acceptablecarriers thereof and optionally other therapeutic agents. Each carriermust be "acceptable" in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient.Formulations include those suitable for oral, rectal, nasal, topical(including transdermal buccal and sublingual), vaginal or parenteral(including subcutaneous, intramuscular, intravenous and intradermal)administration. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association theactive ingredient with the carrier which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and thenif necessary shaping the product.

Compositions suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Such patchessuitably contain the active compound 1) in an optionally buffered,aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3)dispersed in a polymer. A suitable concentration of the active compoundis about 1% to 25%, preferably about 3% to 15%. As one particularpossibility, the active compound may be delivered from the patch byelectrotransport or iontophoresis as generally described inPharmaceutical Research, 3 (6), 318 (1986).

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g. sodium starchglycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) surface-active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile. Tablets may optionally be provided with anenteric coating, to provide release in parts of the gut other than thestomach.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multidose sealed containers, for example, ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose orunit, daily sub-dose, as herein above recited, or an appropriatefraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example, those suitable for oral administration mayinclude such further agents as sweeteners, thickeners and flavoringagents.

The present invention further includes the following process, depictedschematically, for the preparation of compounds of formula (I) above andderivatives thereof either alone or in combination with theircorresponding enantiomers. ##STR3##

Compounds of formulas (I), and (I-1) wherein R⁴ is halogen, e.g.,chloro, may be converted into compounds of formulas (I) and (I-1)wherein R⁴ is SH (or S alkyl) OH (or alkoxide) by methods well known inthe art, for example, by reaction with an alcoholic solution of NaHS (orNaS alkyl) or aqueous NaOH (or alcoholic Na alkoxide), respectively.

Thus, according to a further feature of the present invention we providea process for the preparation of compounds of formulae (I) and (I-1)alone or in combination with their mirror image enantiomers, and theirpharmaceutically acceptable derivatives which comprises (A) reacting##STR4## or the mirror image enantiomer thereof, with a) either acompound of formula R⁴ CO₂ H wherein R⁴ is H, C₁₋₄ alkyl or C₁₋₄perfluoroalkyl preferably at an elevated temperature or a compound offormula R⁴ C(OR)₃ wherein R⁴ is H, C₁₋₄ alkyl or C₁₋₄ perfluoroalkyl andR is C₁₋₄ alkyl, preferably at ambient temperature and in an acidicmedium, to form a compound of formula (I) or (I-1) in which R⁴ is H,C₁₋₄ alkyl or C₁₋₄ perfluoroalkyl; or

b) cyanogen bromide to form a compound of formula (I) or (I-1) in whichR⁴ is NH₂ ; or

c) 1,1'-carbonyl-diimidazole to form a compound of formula (I) or (I-1)in which R⁴ is OH; or

d) 1,1'-thiocarbonyl-diimidazole or thiourea to form a compound offormula (I) or (I-1) in which R⁴ is SH; or

(B)

a) converting a compound of formula (I) or (I-1) in which R⁴ is hydrogeninto a further compound of formula (I) or (I-1) in which R⁴ is adifferent group for example by treatment with an N-(Cl, Br or I)succinimide to form a compound in which R⁴ is Cl, Br or I; or

b) converting a compound of formula (I) or (I-1) in which R⁴ is Cl, Bror I into a further compound of formula (I) or (I-1) in which R⁴ is adifferent group as defined above, for example by treatment with analcoholic NaHS or NaS-C₁₋₄ alkyl, e.g. in alcoholic solution to formcompounds in which R⁴ is SH or C₁₋₄ alkylthio respectively, by treatmentwith for example, aqueous NaOH or alcoholic Na-C₁₋₄ alkoxide to formcompounds in which R⁴ is OH or C₁₋₄ alkoxy or by treatment with a C₁₋₄alkylamine or di-C₁₋₄ alkylamine to form compounds in which R⁴ is C₁₋₄alkylamino or di-C₁₋₄ alkylamino; or

(C) reacting a compound of formula ##STR5## (wherein R⁴ is hydrogen andR⁵, R⁶ and R⁷ are as herebefore defined) or a functional equivalentthereof with a compound of formula ##STR6## wherein R¹, R² and R³ are asdefined above and L is a leaving group, for example anorganosulphonyloxy (e.g. p-toluenesulphonyloxy or methanesulphonyloxy),halogen or triflate (OSO₂ CF₃)group), for example in the presence of abase such as sodium carbonate or sodium hydride in a solvent such asdimethylformamide, advantageously at an elevated temperature e.g.80°-100° C., to form a compound of formula (I) or (I-1) in which R⁴ ishydrogen; and optionally converting a compound of formula (I) or (I-1)into a pharmaceutically acceptable derivative thereof.

Alternatively in process (C) above the compound of formula (IV) may bereplaced with a compound in which the L and R³ groups are replaced witha cyclic sulphate group.

All of the structures shown above are intended to represent theenantiomers depicted as well as their mirror image isomers, as well asmixtures thereof. Thus, the present invention is intended to encompassboth the racemates and the pure enantiomers, substantially free of theirmirror-image isomers.

A compound of formula (I) or (I-1) may be converted into apharmaceutically acceptable ester by reaction with an appropriateesterifying agent, e.g. an acid halide or anhydride. The compound offormula (I) or (I-1) including esters thereof, may be converted intopharmaceutically acceptable salts thereof in conventional manner, e.g.by treatment with an appropriate acid. An ester or salt of an ester offormula (I) or (I-1) may be converted into the parent compound, e.g. byhydrolysis.

The following Examples are intended for illustration only and are notintended to limit the scope of the invention in any way. The term`active ingredient` as used in the examples means a compound of formula(I) or (I-1) or a pharmaceutically acceptable derivative thereof.

EXAMPLE A Tablet Formulations

The following formulations A and B were prepared by wet granulation ofthe ingredients with a solution of povidone, followed by addition ofmagnesium stearate and compression.

    ______________________________________                                        Formulation A                                                                                  mg/tablet                                                                             mg/tablet                                            ______________________________________                                        (a) Active ingredient  250       250                                          (b) Lactose B.P.       210       26                                           (c) Povidone B.P.      15        9                                            (d) Sodium Starch Glycollate                                                                         20        12                                           (e) Magnesium Stearate 5         3                                                                   500       300                                          ______________________________________                                    

    ______________________________________                                        Formulafion B                                                                                  mg/tablet                                                                             mg/tablet                                            ______________________________________                                        (a) Active ingredient  250       250                                          (b) Lactose            150       --                                           (c) Avicel PH 101      60        26                                           (d) Povidone B.P.      15        9                                            (e) Sodium Starch Glycollate                                                                         20        12                                           (f) Magnesium Stearate 5         3                                                                   500       300                                          ______________________________________                                    

    ______________________________________                                        Formulation C.                                                                               mg/tablet                                                      ______________________________________                                        Active ingredient                                                                              100                                                          Lactose          200                                                          Starch           50                                                           Povidone         5                                                            Magnesium stearate                                                                             4                                                                             359                                                          ______________________________________                                    

The following formulations, D and E, were prepared by direct compressionof the admixed ingredients. The lactose used in formulation E was of thedirect compression type (Dairy Crest--"Zeparox").

    ______________________________________                                        Formulation D                                                                                   mg/tablet                                                   ______________________________________                                        Active Ingredient   250                                                       Pregelatinised Starch NF15                                                                        150                                                                           400                                                       ______________________________________                                    

    ______________________________________                                        Formulafion E                                                                               mg/tablet                                                       ______________________________________                                        Active Ingredient                                                                             250                                                           Lactose         150                                                           Avicel          100                                                                           500                                                           ______________________________________                                    

Formulation F (Controlled Release Formulation)

The formulation was prepared by wet granulation of the ingredients(below) with a solution of povidone followed by the addition ofmagnesium stearate and compression.

    ______________________________________                                                            mg/tablet                                                 ______________________________________                                        (a)    Active Ingredient  500                                                 (b)    Hydroxypropylmethylcellulose                                                                     112                                                        (Methocel K4M Premium)                                                 (c)    Lactose B.P.       53                                                  (d)    Povidone B.P.C.    28                                                  (e)    Magnesium Stearate 7                                                                             700                                                 ______________________________________                                    

EXAMPLE B Capsule Formulations

Formulation A

A capsule formulation was prepared by admixing the ingredients ofFormulation D in Example 1 above and filling into a two-part hardgelatin capsule. Formulation B (infra) was prepared in a similar manner.

    ______________________________________                                        Formulation B                                                                                   mg/capsule                                                  ______________________________________                                        (a)    Active ingredient                                                                              250                                                   (b)    Lactose B.P.     143                                                   (c)    Sodium Starch Glycollate                                                                       25                                                    (d)    Magnesium Stearate                                                                             2                                                                             420                                                   ______________________________________                                    

    ______________________________________                                        Formulation C                                                                                 mg/capsule                                                    ______________________________________                                        (a)     Active ingredient                                                                           250                                                     (b)     Macrogol 4000 BP                                                                            350                                                                           600                                                     ______________________________________                                    

Capsules were prepared by melting the macrogol 4000 BP, dispersing theactive ingredient in the melt and filling the melt into a two-part hardgelatin capsule.

    ______________________________________                                        Formulation D                                                                               mg/capsule                                                      ______________________________________                                        Active ingredient                                                                             250                                                           Lecithin        100                                                           Arachis Oil     100                                                                           450                                                           ______________________________________                                    

Capsules were prepared by dispersing the active ingredient in thelecithin and arachis oil and filling the dispersion into soft, elasticgelatin capsules.

Formulation E (Controlled Release Capsule)

The following controlled release capsule formulation was prepared byextruding ingredients a, b and c using an extruder, followed byspheronisation of the extrudate and drying. The dried pellets were thencoated with release-controlling membrane (d) and filled into atwo-piece, hard gelatin capsule.

    ______________________________________                                                          mg/capsule                                                  ______________________________________                                        (a)    Active Ingredient                                                                              250                                                   (b)    Microcrystalline Cellulose                                                                     125                                                   (c)    Lactose BP       125                                                   (d)    Ethyl Cellulose  13                                                                            513                                                   ______________________________________                                    

EXAMPLE C Injectable Formulation

    ______________________________________                                        Formulation A.                                                                ______________________________________                                        Active ingredient     0.200 g                                                 Hydrochloric acid solution, 0.1M                                                                    q.s. to pH 4.0 to 7.0                                   Sodium hydroxide solution, 0.1M                                                                     q.s. to pH 4.0 to 7.0                                   Sterile water         q.s. to 10 ml                                           ______________________________________                                    

The active ingredient was dissolved in most of the water (35°-40° C.)and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid orthe sodium hydroxide as appropriate. The batch was then made up tovolume with the water and filtered through a sterile micropore filterinto a sterile 10 ml amber glass vial (type 1) and sealed with sterileclosures and overseals.

    ______________________________________                                        Formulation B.                                                                ______________________________________                                        Active ingredient        0.125 g                                              Sterile, pyrogen-free, pH 7 phosphate buffer,                                                          q.s. to 25 ml                                        ______________________________________                                    

EXAMPLE D Intramuscular Injection

    ______________________________________                                        Active Ingredient                                                                              0.20 g                                                       Benzyl Alcohol   0.10 g                                                       Glycofurol       1.45 g                                                       Water for Injection                                                                            q.s. to 3.00 ml                                              ______________________________________                                    

The active ingredient was dissolved in the glycofurol. The benzylalcohol was then added and dissolved, and water added to 3 ml. Themixture was then filtered through a sterile micropore filter and sealedin sterile 3 ml amber glass vials (type 1).

EXAMPLE E Syrup

    ______________________________________                                        Active ingredient     0.2500 g                                                Sorbitol Solution     1.5000 g                                                Glycerol              2.0000 g                                                Sodium Benzoate       0.0050 g                                                Flavour, Peach 17.42.3169                                                                           0.0125 ml                                               Purified Water        q.s. to 5.0000 ml                                       ______________________________________                                    

The active ingredient was dissolved in a mixture of the glycerol andmost of the purified water. An aqueous solution of the sodium benzoatewas then added to the solution, followed by addition of the sorbitolsolution and finally the flavour. The volume was made up with purifiedwater and mixed well.

EXAMPLE F Suppository

    ______________________________________                                                               mg/suppository                                         ______________________________________                                        Active Ingredient (631 m)*                                                                              250                                                 Hard Fat, BP (Witepsol H15-Dynamit Nobel)                                                              1770                                                                          2020                                                 ______________________________________                                         *The active ingredient was used as a powder wherein at least 90%, of the      particles were of 631 m diameter or less.                                

One-fifth of the Witepsol H15 was melted in a steam-jacketed pan at 45°C. maximum. The active ingredient was sifted through a 2001 m sieve andadded to the molten base with mixing, using a silverson fitted with acutting head, until a smooth dispersion was achieved. Maintaining themixture at 45° C., the remaining Witepsol H15 was added to thesuspension and stirred to ensure a homogeneous mix. The entiresuspension was passed through a 2501 m stainless steel screen and, withcontinuous stirring, was allowed to cool to 40° C. At a temperature of38° C. to 40° C., 2.02 g of the mixture was filled into suitable, 2 mlplastic moulds. The suppositories were allowed to cool to roomtemperature.

EXAMPLE G Pessaries

    ______________________________________                                                         mg/pessary                                                   ______________________________________                                        Active ingredient (631 m)                                                                        250                                                        Anhydrate Dextrose 380                                                        Potato Starch      363                                                        Magnesium Stearate 7                                                                             1000                                                       ______________________________________                                    

The above ingredients were mixed directly and pessaries prepared bydirect compression of the resulting mixture.

Antiviral Testing

1. Anti-HCMV

Human cytomegalovirus (HCMV) is assayed in monolayers of MRC5 cells(human embryonic lung) in multiwell trays. Activity of compounds isdetermined in the plaque reduction assay, in which a cell monolayer isinfected with a suspension of HCMV. A range of concentrations of thecompound to be tested (of known molarity) is then incorporated into thecarboxymethyl cellulose overlay. Plaque numbers of each concentrationare expressed as percentage of the control and a dose-response curve isdrawn. From this curve the 50% inhibitory concentration (IC₅₀) isestimated.

    ______________________________________                                        Anti-HCMV Activity                                                            Compound      IC.sub.50 (μM)                                               ______________________________________                                        Ex. 4         1.9                                                             Ex. 13        1.0                                                             ______________________________________                                    

2. Anti-HBV

a. Overview:

Anti-HBV activity of compounds of formula (I) and (I-1) was determinedwith a high-capacity assay for assessing efficacy. Supernatants fromgrowing HBV-producing cells (HepG2 2.2.15, P5A cell line) in 96-wellplates are applied to microtiter plate wells which have been coated witha specific monoclonal antibody to HBV surface antigen (HBsAg). Virusparticles present in the supernatants bind to the antibody and remainimmobilized while other debris is removed by washing. These virusparticles are then denatured to release HBV DNA strands which aresubsequently amplified by the polymerase chain reaction and detectedwith a colorimetric hybrid-capture assay. Quantitation is achievedthrough fitting of a standard curve to dilutions of a cell supernatantwith known HBV DNA content. By comparing HBV DNA levels of untreatedcontrol cell supernatants with supernatants containing a compound offormula (I) or (I-1), a measure of anti-HBV effectiveness is obtained.

b. Immunoaffinity Capture of HBV:

HBV producer cells, 2500 cells/well, were seeded in 96-well culturedishes in RPMI/10% fetal bovine serum/2 mM glutamine (RPMI/10/2:). Mediawere replenished on days 1, 3, 5, and 7 with dilutions of a compound offormula (I) or (I-1) in RPMI/10/2 to a final volume of 150 uL. Fifty uLof mouse monoclonal anti-HBsAG antibody (10 ug/mL in PBS) were added toeach well of a round-bottom microtiter plate. After incubation overnightat 4° C., the solutions were aspirated and replaced with 100 uL of 0.1%BSA in PBS. Samples were incubated for 2 hours at 37° C. and washedthree times with PBS/0/01% Tween-20 (PBS/T) using a Nunc Washer. Ten uLof 0.035% Tween 20 in PBS were then added to all wells by Pro/Pette.Cell supernatants (25 uL) containing extracellular virion DNA weretransferred into wells by Pro/Pette; the final Tween concentration is0.01%. Twenty-five uL HBV standard media dilutions in RPMI/10/2 wereadded to 2 rows of wells to serve as an internal standard curve forquantitation, and the plates were sealed and incubated at 4° C.overnight. Samples were washed 5 times with PBS/T and 2 times with PBS,aspirating the last wash. Next, 25 uL of 0.09N NaOH/0.01% NP40 wereadded to each well by Pro/Pette, and the sample wells were sealed andincubated at 37° C. for 60 minutes. Samples were then neutralized with25 uL of 0.09N HCl/100 mM tris (pH 8.3).

c. Polymerase Chain Reaction (PCR):

Polymerase chain reaction (Saiki, R. K. et al., Science, 239 (4839)487-91 (1988)) was carried out on 5 uL samples, using a Perkin Elmer PCRkit. PCR is performed in "MicroAmp tubes" in a final volume of 25 uL.Primers were chosen from conserved regions in the HBV genome, asdetermined by alignment of several sequences. One primer is biotinylatedat the 5-prime end to facilitate hybrid-capture detection of the PCRproducts. All primers were purchased from Synthecell Corp., Rockville,Md. 20850.

d. Hybrid-Capture Detection of PCR Products:

PCR products were detected with horse radish peroxidase-labeledoligonucleotide probes (Synthecell Corp., Rockville, Md. 20850), whichhybridize to biotinylated strands of denatured PCR products directly instreptavidin-coated microtiter plate wells, using essentially the methodof Holodiniy, M. et al., Bio Techniques, 12 (1)37-39 (1992).Modifications included the use of 25λ PCR reaction volumes and sodiumhydroxide denaturation instead of heat. Simultaneous binding of thebiotin moiety to the plate-bound streptavidin during the hybridizationserves to "capture" the hybrids. Unbound labeled probes were washed awaybefore colorimetric determination of the bound (hybridized) horse radishperoxidase. Quantities of HBV DNA present in the original samples werecalculated by comparison with standards. These values were then comparedto those from untreated cell cultures to determine the extent ofanti-HBV activity.

IC₅₀ (the median inhibitory concentration) is the amount of compoundwhich produces a 50 percent decrease in HBV DNA. The approximate IC₅₀ ofthe compounds of Examples 4, 13 and 69 are tabulated.

    ______________________________________                                        Anti-HCMV Activity                                                            Compound      IC.sub.50 (μM)                                               ______________________________________                                        Ex. 4         0.74, 2.5                                                       Ex. 13        5.0                                                             Ex. 69        0.72, 1.3                                                       ______________________________________                                    

e. Selective Inhibition of T Cell Growth:

The compounds of the invention were tested for inhibition of the growthof T cells (Molt 4) and B cells (IM9) by the method of Averett, D.,Journal of Virological Methods. 23, (1989), 263-276.

    ______________________________________                                        Compound       Molt 4 cells                                                                             IM9 cells                                           ______________________________________                                        Ex. 4          39         48                                                  Ex. 13         32         88                                                  Ex. 69         29         35                                                  ______________________________________                                    

Example 1 (±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3R*, 4R*)-tert-ButylN-[2,3-dihydroxy-4-(hydroxymethyl)-1-cyclopentyl]carbamate (6.27 g, 25.1mmol) and 1N hydrochloric acid (50 mL) were stirred overnight. Theresulting clear solution was concentrated in vacuo and dried byevaporation of methanol and ethanol to give the hydrochloride of(±)-(1S*, 2R*, 3S*, 5R*)-3-amino-5-(hydroxy-methyl)-1,2-cyclopentanediolas a solid foam (4.73 g). This solid foam was refluxed vigorously withtriethylamine (7.5 g, 75 mmol), 1,2,4-trichloro-5-nitrobenzene (5.84 g,25.0 mmol as 97%, Aldrich), and 2-methoxyethanol (75 mL) for 24 hours.The resulting black mixture was evaporated to dryness and the residuechromatographed on silica gel and product eluted withmethanol:chloroform/1:10 as a dark orange glass (6.9 g). Crystallizationfrom ethanol-water gave orange powder (3.00 g) which was stirred inacetic anhydride (3.0 mL)-pyridine (20 mL) at ambient temperatureovernight. Evaporation of volatiles, followed by crystallization fromethyl acetate-hexanes gave title compound as orange needles (2.82 g,24%), m.p. 153°-156° C.; ¹ H-NMR (DMSO-d₆)δ: 8.25 and 7.51 (both s, 1each, C₆ H₂), 8.07 (d, J=7.8 Hz, 1, NH), 5.23 and 5.09 (both m, 2, 2CHO), 4.3 (m, 1, CHN), 4.2-4.0 (m, 2, CH₂ O), 2.5-2.35 (m, 2, 2CH),2.04, 2.03, 2.02 (all s, 9, 3CH₃ CO), 1.5-1.4 (m, 1, CH).

Anal. Calcd. for C₁₅ H₂₀ N₂ O₅ Cl₂ : C, 46.67; H, 4.35; N, 6.05; Cl,15.31. Found: C, 46.66; H, 4.37; N, 6.02; Cl, 15.38.

Example 2 (±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate (2.75 g, 5.93 mmol) and Raney nickel (aqueous slurry, Aldrich,300 mg wet) in isopropanol (250 mL) was shaken under hydrogen (40 psi)in a Parr shaker for 2.25 hours. Catalyst was filtered off with Celiteand the filtrate acidified with 98% formic acid (5 mL) and concentratedto an orange oil. The oil was diluted with additional 98% formic acid(45 mL) and the resulting orange solution refluxed for 40 minutes.Volatiles were removed and the remaining dark oil dissolved inchloroform (100 mL). The chloroform solution was washed with saturatedaqueous sodium bicarbonate (3×10 mL), dried (sodium sulfate), andevaporated to a foam which was chromatographed on silica gel. Titlecompound eluted with methanol:chloroform/3:97 as a white foam from ethylacetate (2.26 g, 86%); ¹ H-NMR (DMSO-d₆)δ: 8.57, 8.17, 7.97 (all s, 1each, 3 benzimidazole CH), 5.6 (m, 1, CHO), 5.3-5.1 (m, 2, CHO and CHN),4.35-4.15 (m, 2, CH₂ O), 2.6-2.4 (m overlapping solvent, 2 CH), 2.10,2.06, 1.92 (all s) overlapped by 2.0 (m, total 10, 3CH₃ CO and CH).

Anal. Calcd. for C₁₉ H₂₀ N₂ O₆ Cl₂ : C, 51.49; H, 4.55; N, 6.32; Cl,16.00. Found: C, 51.39; H, 4.58; N, 6.22; Cl, 16.07.

Example 3 (±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (1.32 g, 2.98 mmol) in dry N, N-dimethylformamide (6 mL) washeated to 60° C. Portions (ca. 1 mmol each) of N-bromosuccinimide (1.59g, 8.93 mmol) were added over 5 hours. Heating was continued for anadditional 4 hours. Volatiles were removed in vacuo and the residuechromatographed on silica gel. Title compound eluted with 1:1hexane-ethylacetate as a tan powder (1.1 g, 69%), ¹ H-NMR identical withrecrystallized sample. Such a sample was recrystallized fromethanol-water to a white powder, m.p. 156°-159° C.; ¹ H-NMR (DMSO-d₆)δ:8.34, 7.97 (both s, 1 each, 2 benzimidazole CH), 5.6 (m, 1, OCH), 5.3(m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.4-4.2 (m, 2, OCH₂), 2.7-2.5 (m, 1,CH), 2.4-2.0 (m) overlapping 2.1 and 2.07 (both s, total 8, CH₂ and 2CH₃CO), 1.92 (s, 3, CH₃ CO); mass spectrum (CI): 527 (6.6), 525 (45), 523(100), 521 (65, M+1), 257 (48, M-B).

Anal. Calcd. for C₁₉ H₁₉ N₂ O₆ BrCl₂ : C, 43.71; H, 3.67; N, 5.37; totalhalogen as Br, 45.91. Found: C, 43.64; H, 3.63; N, 5.30; total halogenas Br, 45.77.

Example 4 (±)-(1R*, 2S*, 3S*,5S*)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (600 mg, 1.15 mmol) was added to a stirred mixture of sodiumcarbonate (122 mg) in water (2 mL)-ethanol (10 mL)-methanol (10 mL).After 2.5 hours at ambient temperature, the pH was adjusted to 7 withglacial acetic acid. Volatiles were removed in vacuo and the residuetriturated with water (5 mL) and filtered to give white solid.Recrystallization of the solid from 1:1 ethanol-methanol gave titlecompound as a white powder (282 mg, 62%), m.p. 208°-211° C.; ¹ H-NMR(DMSO-d₆)δ: 8.23, (s, 1, benzimidazole H7), 7.95 (s, benzimidazole H4),5.13 (t, J=4.1 Hz, 1, CH₂ OH), 5.03 (d, J=6.2 Hz, 1, OH), 5.0-4.85 (m,1, H5), 4.71 (d, J=3.5 Hz, 1, OH), 4.55-4.45 (m, 1, H1), 3.85-3.80 (m,1, H2), 3.7-3.6 and 3.55-3.45 (both m, 1 each, OCH₂), 2.2-1.95 (m, 3, H3and 2H4); mass spectrum (CI): 395 (M+1).

Anal. Calcd. for C₁₃ H₁₃ N₂ O₃ Cl₂ Br: C, 39.43; H, 3.31; N, 7.07; totalhalogen as Br, 60.52. Found: C, 39.50; H, 3.33; N, 7.02; total halogenas Br, 60.61.

Example 5 (±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2,5,6-trichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (850 mg, 1.92 mmol) in dry N,N-dimethylformamide (5 mL) wasmaintained at 95° C. while N-chlorosuccinimide (760 mg) was added inportions over 3 hours. Heating was continued for a total of 6 hours.Volatiles were removed in vacuo and the residue chromatographed onsilica gel. Title compound was eluted with ethyl acetate:hexanes/3:7 asa yellow solid (160 mg, 17%), ¹ H-NMR consistent with structure andalmost identical with that of title compound of Example 3.

Example 6 (±)-(1R*, 2S*, 3S*,5S*)-5-(2,5,6-trichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2,5,6-trichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (160 mg, 3.40 mmol) was deblocked as in Example 4 to give,after elution from a silica gel compound, title compound as whitepowder, (36 mg, 31%), m.p. 206°-210° C.; ¹ H-NMR (DMSO-d₆)δ: 8.24 (s, 1,benzimidazole H7), 7.98 (s, 1, benzimidazole H4), 5.15-5.0 (m, 2, CH₂ OHand OH), 5.0-4.8 (m, 1, H5), 4.74 (d, J=3.5 Hz, 1, OH), 4.55-4.40 (m, 1,H1), 3.9-3.75 (m, 1, H2), 3.7-3.4 (m, 2, OCH₂), 2.2-1.9 (m, 3, H3 and2H4).

Anal. Calcd. for C₁₃ H₁₃ N₂ O₃ Cl₃ : C, 44.41; H, 3.73; N, 7.97; Cl,30.25. Found: C, 44.20; H, 3.81; N, 7.94; Cl, 30.08.

Example 7 (1α,3β,4β)-(3,4-Dihydroxy-1-cyclopentyl) methyl benzoate

To a stirred, cooled (0° C.) solution of 4-hydroxymethylcyclopentene (J.-P. Depres and A. E. Green, J. Org. Chem. 1984, 49, 928-931, andreferences therein) (37.0 g, 276 mmol) in pyridine (450 mL) was addedbenzoylchloride (32.1 mL, 276 mmol) over 30 minutes. The resultingmixture was stirred at room temperature for 1.25 hours. Water (50 mL)was added and the volatiles removed in vacuo. The residual oil wasdissolved in chloroform and the solution extracted with water and thendried over sodium sulfate. Evaporation of solvent gave(3-cyclopenten-1-yl)methylbenzoate as a yellow oil (53.94 g, 91%),sufficiently pure for use; ¹ H-NMR (DMSO-d₆)δ: 7.98, 7.67, 7.56 (m, 5,C₆ H₅), 5.72 (s, 2, CH═CH), 4.19 (m, 2, OCH₂), 2.71 (m, 1, CH),2.56-2.77 (m, overlapping solvent, 2CH), 2.21-2.14 (m, 2, 2CH).

(3-Cyclopenten-1-yl)methyl benzoate (37.6 g, 0.161 mol) in acetone (200mL) was added dropwise over 2 hours to a stirred solution ofN-methylmorpholine-N-oxide (33.1 g, 60% in water, 0.169 mol), osmiumtetroxide (2.5% in t-butanol, Aldrich, 3.0 mL), and acetone (200 mL) atambient temperature. Stirring was continued for an additional 16 hours.Chloroform (500 mL) and water (150 mL) were added. The organic layer wasseparated, washed with cold 1N hydrochloric acid (2×150 mL) and thenwith saturated aqueous sodium bicarbonate (100 mL) and dried (MgSO₄).Volatiles were removed and the residual solid crystallized from toluene(200 mL) to give title compound as white crystals (26.9 g, 73%), m.p.92°-94° C.; ¹ H-NMR (DMSO-d₆)δ: 7.96, 7.65, 7.56 (m, 5, C₆ H₅), 4.38 (d,J=4.1 Hz, 2, 2OH), 4.14 (d, J=6.6 Hz, 2, CH₂ O), 3.90 (m, 2, 2 OCH),2.58 (m overlapping solvent, CH), 1.75 (m, 2, 2CH), 1.55 (m, 2, 2CH).

Anal. Calcd. for C₁₃ H₁₆ O₄ : C, 66.09; H, 6.83. Found: C, 66.19; H,6.86.

Concentration of mother liquors yielded 10.33 g of white solid whichcontained additional title compound contaminated by (±)-(1₋₋, 3₋₋,4₋₋)-(3,4-dihydroxy-1-cyclopentyl)methyl benzoate, ratio approximately2:3 by ¹ H-NMR.

Example 8 (3a-α, 5α,6a-α)-(Tetrahydro-4H-cyclopenta-1,3-2-dioxathiol-5-yl)methyl benzoateS-oxide

Thionyl chloride (6.04 g, 50.8 mmol) was added to a solution of (1β, 3α,4α)-(3,4-dihydroxy-1-cyclopentyl)methyl benzoate (10.0 g, 42.3 mmol) incarbon tetrachloride (150 mL). The solution was refluxed for 1.5 hours.Solvent was evaporated to leave title compound as a thick oilsufficiently pure for use (see following example). Such a samplecrystallized as a waxy solid from toluene, m.p. 48°-57° C.; ¹ H-NMR(DMSO-d₆)δ: 7.96, 7.66, 7.52 (m, 5, C₆ H₅), 5.46 and 5.32 (both m, 1, 2OCH, due to ca 1:1 mixture of isomeric S-oxides), 4.28 (m, 2, OCH₂),2.90 and 2.43 (both m, 1, CH of two isomeric S-oxides), 2.10 and 1.74(both m, 4, 4CH).

Anal. Calcd. for C₁₃ H₁₄ O₅ S: C, 55.31; H, 5.00; S, 11.36. Found: C,55.41; H, 5.04; S, 11.30.

Example 9 (3a-α, 5α,6a-α)-(Tetrahydro-4H-cyclopenta-1,3-2-dioxathiol-5-yl)methyl benzoate S,S-dioxide

(3a-α, 5α, 6a-α)-(Tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl)methylbenzoate S-oxide (previous example, 42.3 mmol) was stirred in carbontetrachloride (40 mL)-acetonitrile (40 mL)-water (60 mL) while sodiummetaperiodate (8.98 g, 42.3 meq) and ruthenium trichloride (44 mg, 0.21meq) were added. Additional sodium metaperiodate (179 mg) was addedafter 30 minutes to bring the reaction to completion as judged by TLC(silica gel, methanol:chloroform/1:19, visualized in iodine). After atotal of 1.0 hour, methylene chloride (300 mL) was added. The organiclayer was separated and the aqueous layer extracted with additionalmethylene chloride (300 mL). The combined organic layers were washedwith saturated aqueous sodium bicarbonate (100 mL), then saturatedaqueous sodium chloride (100 mL), dried (MgSO₄) and concentrated invacuo to give title compound as white powder (12.37 g, 98%), m.p.114°-119° C.; ¹ H-NMR (DMSO-d₆)δ: 8.02, 7.70, 7.55 (all m, 5, C₆ H₅),5.62 (m, 2, OCH), 4.34 (d, J=5.8 Hz, 2, OCH₂), 2.79-2.64 (m, 1, CH),2.32-2.21 and 1.97-1.79 (m, 4, 2 CH2).

Anal. Calcd. for C₁₃ H₁₄ SO₆ : C, 52.35; H, 4.73; S, 10.75. Found: C,52.32; H, 4.73; S, 10.69.

Example 10 (±)-(1R*, 2R*,4S*)-2-(5,6-Dichloro-1H-benzimidazol-1-yl)-4-(hydroxymethyl)cyclopentanol

Sodium hydride (416 mg, 10.4 meq as 60% oil dispersion) was added to asolution of 5,6-dichlorobenzimidazole (L. B. Townsend and G. R.Revankar, Chem. Rev. 1970, 70, 389, and references therein) (1.50 g,8.00 mmol) in dry N,N-dimethylformamide (35 mL). The mixture was stirredfor 45 minutes at 25° C. (3a-α, 5α,6a-α)-(tetrahydro-4H-cyclopenta-1,3-2-dioxathiol-5-yl)methyl benzoate S,S-dioxide (3.05 g, 10.2 mmol) was added in portions over 5 hours.Stirring was continued overnight at ambient temperature. Volatiles wereremoved in vacuo and the residual oil dissolved in 1,4-dioxane (130mL)-water (10 mL) at reflux with 4M sulfuric acid (2.3 mL). After 10minutes at reflux, the solution was basified with 5N sodium hydroxide,heated for an additional hour at 50° C., and then neutralized withadditional acid. Evaporation of volatiles in vacuo gave residual solidswhich were extracted with chloroform to remove unreacted5,6-dichlorobenzimidazole and then crystallized from ethanol-water togive title compound as white powder (2.09 g, 87%). Recrystallization ofsuch a sample from ethanol-water gave title compound as white granules,m.p. 244°-245° C.; ¹ H-NMR (DMSO-d₆)δ: 8.47, 8.05, 7.93 (all s, 3, arylCH), 5.19 (d, J=5.3 Hz, 1, CHOH), 4.71 (t, J=5.3 Hz, 1, CH₂ OH), 4.6-4.5(m, 1, NCH), 4.37-4.25 (m, 1, OCH), 3.41 (m, 2, OCH₂), 2.4-2.2 and1.95-1.62 (m, 5, 5CH).

Anal. Calcd. for C₁₃ H₁₄ N₂ O₂ Cl₂.0.02 C₂ H₅ OH: C, 51.85; H, 4.71; N,9.27; Cl, 23.47. Found: C, 51.87; H, 4.74; N, 9.28; Cl, 23.60.

Example 11 (±)-(1R*, 2R*,4S*)-4-(Acetoxymethyl)-2-(5,6-dichloro-1H-benzimidazol-1-yl) cyclopentylacetate

(±)-(1R*, 2R*,4S*)-2-(5,6-Dichloro-1H-benzimidazol-1-yl)-4-(hydroxymethyl)cyclo-pentanol (7.80 g, 25.8 mmol) was dissolved in pyridine (50mL)-acetic anhydride (50 mL) and the solution stirred overnight.Volatiles were removed in vacuo and the residual oil partitioned betweenmethylene chloride (150 mL) and saturated aqueous sodium bicarbonate(100 mL). The organic layer was dried (sodium sulfate) and evaporated toa glass (9.91 g, 99%); ¹ H-NMR (DMSO-d₆)δ: 8.58, 8.08, 7.96 (s, 3, arylCH), 5.39-5.32 (m, 1, OCH), 5.09-5.04 (m, 1, NCH), 4.11 (d, J=6.6 Hz, 2,OCH₂), 2.59-2.50 (m overlapping solvent, CH), 2.41-2.35 (m, 1, CH),2.17-1.86 (m overlapping 2.06 and 1.94, both s, total 9, 3CH and 2CH₃CO).

Anal. Calcd. for C₁₇ H₁₈ N₂ O₂ Cl₂.0.1 CH₂ Cl₂ : C, 52.96; H, 4.70; N,7.26; Cl, 18.55. Found: C, 52.86; H, 4.74; N, 7.25; Cl, 18.50.

Example 12 (±)-(1R*, 2R*,4S*)-4-(Acetoxymethyl)-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-cyclopentylacetate

N-Bromosuccinimide (4.54 g, 25.5 mmol) was added to a solution of(±)-(1R*, 2R*,4S*)-4-(acetoxymethyl)-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclopentylacetate (8.95 g, 23.2 mmol) in dry N,N-dimethylformamide (46 mL). Thesolution was maintained at ca. 70° C. (oil bath) for 5 hours. Volatileswere removed in vacuo and the residual orange syrup chromatographed onsilica gel. Title compound was eluted with chloroform as a pale yellowsolid (5.14 g, 48%), m.p. 122°-125° C.; ¹ H-NMR (DMSO-d₆)δ: 8.16 (s, 1,benzimidazole H7), 7.95 (s, 1, benzimidazole H4), 5.60-5.55 (m, 1, OCH),5.12-5.03 (m, 1, NCH), 4.15 (d, J=6.3 Hz, 2, OCH₂), 2.66-2.60 (m, 1,CHCH₂), 2.29-2.14 (m, 3, CH), 2.06 (s, 3, CH₃ CO), 1.93 (s overlapped bym, 4, CH₃ CO+CH); mass spectrum (CI): 469 (5.8), 467 (37.5), 465 (95),463 (54, M+1), 199 (100, M-B).

Anal. Calcd. for C₁₇ H₁₇ N₂ Cl₂ BrO₄ : C, 43.99; H, 3.69; N, 6.04; totalhalogen as Br, 51.65. Found: C, 44.06; H, 3.70; N, 5.97; total halogenas Br, 51.74.

Example 13 (±)-(1R*, 2R*,4S*)-2-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-4-(hydroxymethyl)cyclo-pentanol

(±)-(1R*,2R*,4S*)-4-(Acetoxymethyl)-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-cyclopentylacetate (2.75 g, 5.92 mmol) was added to a stirred mixture of sodiumcarbonate (0.63 g) in water (11 mL)-ethanol (55 mL)-methanol (55 mL).After 2 hours at ambient temperature, the pH was adjusted to 7 withglacial acetic acid. Volatiles were removed in vacuo and the residuetriturated with water (30 mL) and filtered to give white solid.Recrystallization of the solid from 1:1 ethanol-methanol gave titlecompound as white powder (1.62 g, 72%), m.p. 218°-220° C.; ¹ H-NMR(DMSO-d₆)δ: 8.18 (s, 1, benzimidazole H7), 7.97 (s, 1, benzimidazoleH4), 5.20 (m, 1, OH), 4.95 (m, 1, OH), 4.80-4.60 (m, 2, OCH and NCH),3.50-3.40 (m, 2, OCH₂), 2.45-2.20 (m, 1, CH), 2.20-1.60 (m, 4, 4CH);mass spectrum (CI): 379 (M+1).

Anal. Calcd. for C₁₃ H₁₃ N₂ O₂ Cl₂ Br: C, 41.08; H, 3.45; N, 7.37; totalhalogen as Br, 63.07. Found: C, 41.27; H, 3.49; N, 7.28; total halogenas Br, 62.88.

Example 14 (±)-(1R*, 2S*, 3R*)-3-Azido-1,2-cyclopentanediol

(±)-(1R*, 2R*, 3S*)-2,3-Epoxy-1-cyclopentanol (R. Steyn and H. Z. Sable,Tet 1969, 25, 3579) (36.2 g, 0.362 mol), sodium azide (47.1 g, 0.724equiv), ammonium sulfate (23.9 g, 0.181 equiv), dioxane (200 mL) andwater (180 mL) were slowly brought to reflux. After an initial exothermhad subsided, the solution was refluxed gently for 18 hours. Volatileswere removed and residual material extracted with absolute ethanol (250mL). The ethanol was evaporated and the residual oil chromatographed onsilica gel. Title compound eluted with methylene chloride as a paleyellow oil (41.0 g, 79%); ¹ H-NMR (DMSO-d₆)δ: 4.96 (d, J=6.4 Hz, 1, OH),4.55 (d, J=3.9 Hz, 1, OH), 3.85-3.55 (m, 3, 2 OCH and NCH), 2.1-1.75 and1.55-1.2 (m, 4, 2CH₂).

Anal. Calcd. for C₅ H₉ N₃ O₂ : C, 41.95; H, 6.34; N, 29.35. Found: C,41.71; H, 6.36; N, 29.15. Continued elution of the column with methylenechloride gave 5.32. g of oil which consisted of additional titlecompound contaminated by ca. 50% of (±)-(1α, 2β,3α)-2-azido-1,3-cyclo-pentanediol.

Example 15 (±)-(1R*, 2S*, 3R*)-3-Amino-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3R*)-3-Azido-1,2-cyclopentanediol (2.10 g, 14.7 mmol), 5%palladium on carbon (250 mg) and absolute ethanol (150 mL) were shakenon a Parr shaker under hydrogen (50 psi) for 3 hours. The catalyst wasfiltered (Celite) and solvent evaporated in vacuo to give title compoundas white solid (1.65 g, 96%), m.p. 74°-76° C.

Anal. Calcd. for C₅ H₁₁ NO₂ : C, 51.26; H, 9.46; N, 11.96. Found: C,51.16; H, 9.52; N, 11.91.

Example 16 (±)-(1R*, 2S*,3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3R*)-3-Amino-1,2-cyclopentanediol (7.10 g, 50.0 mmol),1,2,4-trichloro-5-nitrobenzene (11.67 g, 50.0 mmol as 97%, Aldrich),triethylamine (10 mL) and t-butanol (50 mL) were refluxed under nitrogenfor 7 hours. Volatiles were removed in vacuo and the black residuechromatographed on silica gel. Title compound was eluted withmethanol:chloroform/1:24 as an orange solid (6.45 g, 42%).Crystallization of such a sample from ethanol-water gave title compoundas yellow needles, m.p. 137°-140° C.; ¹ H-NMR (DMSO-d₆)δ: 8.26 and 7.49(both s, 1 each, 2 aromatic CH), 8.06 (d, J=7.0 Hz, 1, NH), 5.04 (d,J=6.1 Hz, 1, OH), 4.65 (d, J=4.1 Hz, 1, OH), 4.0-3.7 (m, 3, 2 OCH andNCH), 2.2-2.21, 2.0-1.8, 1.7 -1.3 (all m, 4, 4 CH).

Anal. Calcd. for C₁₁ H₁₂ N₂ O₄ Cl₂ : C, 43.02; H, 3.94; N, 9.12; Cl,23.09. Found: C, 43.01; H, 3.92; N, 9.04; Cl, 23.15.

Example 17 (±)-(1R*, 2S*,3R*)-3-(2-Amino-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclopentanediol(2.00 g, 6.51 mmol) in ethanol (100 mL) was shaken in a Parr shaker withRaney nickel (Aldrich, prewashed with water until neutral, ca. 1 tsp)under hydrogen (50 psi) for 1.5 hours, at which point uptake of hydrogenhad ceased. TLC (silica gel, methanol:chloroform/1:10) shows one spot atlower R_(f) than starting material. The catalyst was filtered off(Celite) and volatiles evaporated to leave a glass (2.0 g) whichdarkened readily in air. It was immediately dissolved in acetonitrile(20 mL) and cyanogen bromide (1M in acetonitrile, Aldrich, 1.4 mL, 7.0mmol) was added and the solution stirred under nitrogen at ambienttemperature overnight. The dark precipitate which formed dissolved onaddition of water (20 mL). The purple solution was neutralized with 1Nsodium hydroxide. The resulting precipitate was filtered off, washedwith water, and crystallized form 95% ethanol (75 mL) to give gray-whitepowder (1.14 g, 58%), m.p. >250° C. dec; ¹ H-NMR (DMSO-d₆)δ: 7.37 and7.32 (both s, 2, 2 benzimidazole CH), 6.6 (br s, 2, NH₂), 4.81 (d, J=7.3Hz, 1, OH), 4.73 (d, J=3.2 Hz, 1, OH), 4.7-4.5 (m, 1, NCH), 4.4 (m, 1,OCH), 2.4-1.6 (m, 4, 4 CH).

Anal. Calcd. for C₁₂ H₁₃ N₃ O₂ Cl₂ : C, 47.70; H, 4.34; N, 13.91; Cl,23.47. Found: C, 47.80; H, 4.35; N, 13.83; Cl, 23.45.

Example 18 (±)-(1R*, 2S*,3R*)-3-(5,6-Dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3R*)-3-(4,5-Dichloro-2-nitroanilino)1,2-cyclopentanediol(2.00 g, 6.51 mmol) was stirred in acetic anhydride (1.8 mL)-pyridine(15 mL) at ambient temperature overnight. Volatiles were removed invacuo. The residual oil was partitioned between saturated aqueous sodiumbicarbonate and H₂ O. The CHCl₃ layer was dried (Na₂ SO₄) and solventevaporated to a yellow solid (2.56 g). This diacetate was reduced withRaney nickel under hydrogen as in Example 17. Catalyst was filtered offand 98% formic acid (5 mL) was added to the ethanol filtrate. Volatileswere removed in vacuo and the residue refluxed in 98% formic acid (35mL) for 30 minutes. The formic acid was evaporated and the residual oilpartitioned between chloroform and excess saturated aqueous sodiumbicarbonate. The chloroform layer was dried (Na₂ SO₄) and concentratedto a brown oil. The oil was chromatographed on silica gel. Titlecompound eluted with 6-10% methanol-chloroform. Crystallization fromethanol-water gave title compound as white powder (1.77 g, 72%), m.p.95°-97° C.; ¹ H-NMR (DMSO-d₆)δ: 8.56, 8.16, 7.96 (all s, 1 each, 3benzimidazole CH), 5.6-5.5 (m, 1, OCH), 5.35-5.30 (m, 1, OCH), 5.15-5.05(m, 1, NCH), 2.55-2.25 (m, overlapping solvent, 2 CH), 2.1-2.0 (m,overlapping s at 2.10, 4, CH and CH₃ CO), 2.0-1.8 (m, overlapping s at1.88, 4, CH and CH₃ CO).

Anal. Calcd. for C₁₆ H₁₆ N₂ O₄ Cl₂.0.45 H₂ O: C, 50.66; H, 4.49; N,7.39; Cl, 18.69. Found: C, 50.73; H, 4.49; N, 7.36; Cl, 18.70.

Example 19 (±)-(1R*, 2S*,3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*,3R*)-3-(Dichloro-1H-benzimidazol-1-yl)-1,2,-cyclopentanediyl diacetate(800 mg, 2.16 mmol) was brominated as in Example 3 and the titlecompound eluted from a silica gel column with ethyl acetate:hexanes/3:7as a white powder (450 mg, 46%). Such a sample was resolidified fromEtOAc-hexanes to give title compound as white powder, m.p. 140°-146° C.;¹ H-NMR (DMSO-d₆)δ: 8.24 and 7.96 (both s, 1 each, H7 and H4), 5.8-5.7(m, 1, OCH), 5.4-5.3 (m, 1, OCH), 5.2-5.1 (m, 1, NCH), 2.6-2.4 (m,overlapping solvent, CH), 2.4-2.15 (m, 2, 2 CH), 2.11 (s, 3, CH₃ CO),1.95-1.80 (m overlapping s at 1.88, 4, CH and CH₃ CO); mass spectrum(CI): 455 (1.3), 453 (29), 451 (68), 449 (45, M+1).

Anal. Calcd. for C₁₆ H₁₅ N₂ O₄ Cl₂ Br: C, 42.70; H, 3.36; N, 6.22; totalhalogen as Cl, 23.63. Found: C, 42.77; H, 3.41; N, 6.16; total halogenas Cl, 23.68.

Example 20 (±)-(1R*, 2S*,3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2,-cyclopentanediol

The diacetate of Example 19 (315 mg, 0.700 mmol) was deblocked as inExample 4, with chromatography of the crude product on silica gel. Titlecompound was eluted with methanol:chloroform/1:9 as white powder (180mg, 74%), m.p. 169°-175° C.; ¹ H-NMR (DMSO-d₆)δ: 7.99 and 7.95 (both s,2, 2 benzimidazole CH), 5.08 (d, J=6.3 Hz, 1, OH), 5.0-4.85 (m, 1, NCH),4.76 (d, J=3.0 Hz, 1, OH), 4.55-4.45 (m, 1, OCH), 4.05-3.95 (m, 1, OCH),2.35-2.0 (m, 3, 3CH), 1.7-1.6 (m, 1, CH).

Anal. Calcd. for C₁₂ H₁₁ N₂ Cl₂ O₂ Br: C, 39.20; H, 3.06; N, 7.62; totalhalogen as Cl, 28.93; Found: C, 38.99; H, 3.07; N, 7.49; total halogenas Cl, 29.16.

Example 21 (-)-(1S, 4R)-4-Amino-2-cyclopentene-1-carboxylic acidmethanesulfonate

A solution of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (97.45 g, 0.8929mol, Enzymatix Ltd.) in tetrahydrofuran (500 mL) was filtered and warmedto 35° C. A solution of methanesulfonic acid (63.7 mL, 0.9817 mol) inwater (24.1 mL, 1.34 mol) was added over the course of 1.5 hours suchthat the ensuing exotherm did not exceed 45° C. The resulting slurry washeated at 60° C. for three hours, then allowed to cool to roomtemperature over the course of 15 hours. The slurry was filtered and thecake washed twice with anhydrous tetrahydrofuran (200 mL). An analyticalsample of the wet cake was removed and dried to give the title compoundas a white solid (1.264 g); m.p. 167°-169.2° C.; ¹ H-NMR (DMSO-d₆)δ:12.6 (br s, 1H, CO₂ H), 8.04 (br s, 3H, NH₃ ⁺), 6.10 (dr, J=5.6, 2.0,2.0 Hz, 1H, vinyl), 5.85 (dt, J=5.3, 2.3, 2.3Hz, 1H, vinyl), 4.19 (br s,w1/2=20Hz, 1H, allylic H), 3.61 (m, w1/2=22Hz, 1H, allylic H), 2.53(quintet, J=5.3 Hz (overlapping with DMSO peak), 1/2CH₂), 2.39 (s, 3H,CH₃ SO₃ H), 1.93 (dt, J=6.7, 6.7, 13.7 Hz, 1H, 1/2CH₂); [α]²⁰ ₅₈₉-83.8°, [α]²⁰ ₅₇₈ -87.4°, [α]²⁰ ₅₄₆ -101.2°, [α]²⁰ ₄₃₆ -186.7°, [α]²⁰₃₆₅ -316.2° (c=1.42, methanol); CI-MS (CH₄): 128(M+1); EI-MS: 127(M).

Anal. Calcd. for C₇ H₁₃ NO₅ S: C, 37.66, H, 5.87; N, 6.27; S, 14.36.Found: C, 37.65; H, 5.88; N, 6.30; S, 14.44.

The remaining wet cake was used directly in the following example.

Example 22 (-)-(1S, 4R)-4-Amino-2-cyclopentene-1-methanol

The tetrahydrofuran-wet cake of (-)-(1S,4R)-4-amino-2-cyclopetene-1-carboxylic acid methanesulfonate prepared inExample 21 was suspended in dry tetrahydrofuran (400 mL) and transferredvia cannula to a rapidly stirring solution of lithium aluminum hydridein tetrahydrofuran (1.0 molar, 1600 mL, 1.6 mol, Aldrich) cooled in anice/acetone bath. The rate of transfer was limited to control the rateof gas evolution and to keep the temperature between 0° and 10° C.(total time of addition 1.5 hours). The resulting mixture was warmed toreflux over the course of two hours, then refluxed for 16 hours.

Approximately 1.6 L of solvent was removed by distillation, theresulting slurry was cooled in an ice-acetone bath, then treated withdiethyl ether (dry, 1 L) and sodium fluoride (403.3 g, 9.605 mol,Aldrich). Water (86 mL, 4.8 mol) was added slowly at such a rate (threehours) that the temperature was kept below 5° C. and the hydrogenevolution was moderated. The resulting slurry was filtered and the cakewashed with tetrahydrofuran (200 mL), then 7% water-tetrahydrofuran (500mL). Quantitative HPLC analysis (see Example 23, below) of the filtrateshowed it to contain 60.04 g of the title compound. The cake wasreslurried in 7% water-tetrahydrofuran (1 L) for a half hour, filtered,and washed with 7% water-tetrahydrofuran (400 mL), then 10%water-tetrahydrofuran (300 mL). Quantitative HPLC analysis (see Example23, below) of the filtrate showed it to contain 26.70 g of the titlecompound. The cake was reslurried in methanol (1 L) for 16 hours,filtered, and washed with methanol (500 mL). Quantitative HPLC analysis(see Example 23, below) of the filtrate showed it to contain 4.09 g ofthe title compound. The total yield of the title compound was thus 90.83g, 0.8027 mol, or 90.5% of theoretical yield corrected for theanalytical sample removed.

Example 23 Analysis of (-)-(1S, 4R)-4-Amino-2-cyclopentene-1-methanoland its enantiomer, (+)-(1R, 4S)-4-amino-2-cyclopentene-1-methanol

Samples of the title compounds were characterized by the method ofBruckner, H., Wittner, R., and Godel, H., "Automated Enantioseparationof Amino Acids by Derivatization with o-Phthaldialdehyde and N-AcylatedCysteines", J. Chrom., 476 (1989) 73-82. Using o-phthaldialdehyde andN-acetyl-L-cysteine as derivatizing reagents. The chromatographicseparation used an Optima II ODS 100×4.5 mm, 3 μm column (III SuppliesCo., Meriden, Conn.) and gradient elution at 0.9 mL/min using initially100% sodium acetate buffer, 40 mM, pH 6.5, with a linear ramp to 18%acetonitrile over 15 minutes and a subsequent hold at 18% acetonitrilefor 15 minutes. Detection was at 338 nm. Samples were dissolved in 0.1molar borate buffer, pH 10.4. The identity and purity of the samples wasestablished by comparison with authentic standards (see EP 434450 (Jun.26, 1991)). The retention time of the (1S, RS) isomer was about 21minutes. The retention time of the (1R, 4 S)-isomer was about 22minutes.

Example 24 (-)-(1R, 4S)-tert-ButylN-[4-hydroxymethyl)-2-cyclopenten-1-yl]carbamate

The first filtrate of Example 22 containing(-)-(1S,4R)-4-amino-2-cyclopentene-1-methanol was cooled in anice-acetone bath and treated with di-tert-butyl dicarbonate (199.42 g,0.9265 mol, Aldrich). The mixture was concentrated under vacuum to avolume of 300 mL, and added to the second filtrate of Example 22 thathad meanwhile been cooled in an ice-acetone bath. The mixture wasallowed to stir and warm to room temperature over the course of 18hours, during which time gas evolved and a clear solution formed. Thissolution was combined with the last filtrate of Example 22 which hadbeen evaporated under vacuum to a mixture of oil and solids. Theresulting solution was evaporated under vacuum to an oil. The oil waspartitioned between ethyl acetate (300 mL) and phosphate buffer (100 mLof 1.5 molar potassium dihydrogen phosphate adjusted to pH 7.0 with 50%sodium hydroxide-water). The phases were separated, the aqueous phasewas reextracted twice with ethyl acetate (200 mL). The organic phaseswere dried over sodium sulfate and filtered through silica gel (50 g.).The solvent was removed under vacuum to give an oil (220.78 g), whichwas taken up in hexanes (300 mL). A minimum amount of ethyl acetate(about 50 mL) was added in order to dissolve the oil, and the solutionwas set to crystallize over the course of three days. The crystals werefiltered off, washed with 20% ethyl acetate/hexanes, and dried bysuction to a constant weight (156.1 g, 0.732 mol, 82.6% of theory) ofthe title compound; m.p. 73°-73.7° C.; ¹ H-NMR (DMSO-d₆)δ: 6.72 (d,J=7.9 Hz, 1H, NH), 5.80 and 5.60 (two m, 2H, CH═CH), 4.59 (t, J=5.2 Hz,1H, OH), 4.45 (m, 1H, CHN), 3.35 (m, overlapping H₂ O, CH₂ O), 2.60 (m,1H, CH), 2.30 (m, 1H, 1/2CH₂), 1.40 (s, 9H, C(CH₃)₃), 1.2 (m, 1H,1/2CH₂); [α]²⁰ ₅₈₉ -2.78°, [α]²⁰ ₅₇₈ -2.84°, [α]²⁰ ₅₄₆ -3.06°, [α]²⁰ ₄₃₆-3.39°, [α]²⁰ ₃₆₅ -0.95° (c=5.07, methanol); CI-MS (CH₄) 214 (M+1); TLC(silica, 10% methanol-chloroform, iodine visualization), R_(f) =0.51.

Anal. Calcd. for C₁₁ H₁₉ O₃ N: C, 61.95; H, 8.98, N, 6.57. Found: C,61.87; H, 8.96; N, 6.59.

An additional 10.14 g of crystalline material was recovered from themother liquor by crystallization and chromatography, bringing the totalyield to 166.24 g (0.780 mol, 87.9% of theory from the lactam startingmaterial of Example 21).

It was also found convenient to prepare the title compound directly from2-azabicyclo [2.2.1]hept-5-en-3-one, either racemic or the (-)enantiomer, as follows. (-)-2-Azabicyclo [2.2.1]hept-5-en-3-one (6.00 g,55.0 mmol) in anhydrous tetrahydrofuran (30 mL) was warmed to 34° C. andstirred while methanesulfonic acid (3.6 mL, 55 mmol) and water (0.99 mL,55 mmol) were added dropwise over 10 minutes. An exotherm of 10° C. wasobserved within 5 minutes and a crystalline solid began to precipitate.The mixture was refluxed (oil bath at 74° C.) for 2.5 hours. The mixturewas cooled to -10° C. and a solution of lithium aluminum hydride (1.0Min tetrahydrofuran, 100 mL) added. The first 15 mL was added over 10minutes and an exotherm of 7° C. noted. The remaining 85 mL was addedrapidly with no further exotherm noted. The mixture was brought toreflux over 30 minutes and reflux continued for 18 hours. The mixturewas cooled to 25° C. and sodium fluoride (25.2 g, 0.600 mole) was addedand, after stirring for 30 minutes water (5.3 mL) was added dropwiseover 10 minutes to the cooled (0° C.) mixture. The mixture was stirredfor 30 minutes at 25° C. and di-tert-butyl dicarbonate (12.6 mL, 55.0mmol) was added. This mixture was stirred for 16 hours, filtered, andthe cake triturated with ethyl acetate (2×50 mL). The combinedfilterate-wash was washed with water (20 mL), dried (Na₂ SO₄),evaporated, and the residual syrup crystallized from ethylacetate:hexanes/1:2 (30 mL) to give title compound as white crystals(10.32 g, 88%), identical in properties to the above-described sample.

Example 25 (-)-(1R, 2S, 3R, 4R)-tert-ButylN-[2,3-dihydroxy-4-(hydroxymethyl)-1-cyclopentyl]carbamate

To a mixture of N-methyl morpholine-N-oxide (146.2 g, 60% in water,0.749 mol) and osmium tetroxide (9.75 g, 2.5% in tert-butanol, 0.959mmol) in acetone (1 L) stirring at -8° C. in an ice-acetone bath wasadded in one portion (-)-(1R, 4S)-tert-butylN-[4-hydroxymethyl)-2-cyclopenten-1-yl]carbamate (152.10 g, 0.7132 mol,from Example 24). The resulting mixture was allowed to warm to roomtemperature over 16 hours, during which time it became homogeneous. Moreosmium tetroxide was added (2.602 g, 0.256 mmol), and the solution wasstirred at 20° C. for four hours, then 40° for two hours, at which timethe reaction was judged complete by TLC (silica, 10%methanol-chloroform, visualization with iodine followed by vanillinchar, starting material: R_(f) =0.51, products: R_(f) =0.22, (2S,3R)-isomer, and R_(f) =0.36, (2R, 3S)-isomer). The ratio of (2S,3R)/(2R, 3S) isomers was about 73:27 as judged by ¹ H-NMR and TLC. Water(75 mL) was added, followed by chloroform (2 L). The resulting two-phasemixture was cooled in an ice bath, and with very gentle agitation (todiscourage phase mixing), anhydrous copper sulfate (457.8 g, Alfa) wasadded in several portions. The resulting slurry was allowed to stir atroom temperature about 16 hours, then was filtered with filter aids(Celite 545 and 512). The cake was washed with tetrahydrofuran (6 L)until no more product eluted. The filtrate was evaporated under vacuumto a dark oil substantially free of N-methyl morpholine. The oil wasfiltered through silica gel (300 g), and eluted with tetrahydrofuran (3L) until all of the product was eluted. The eluate was concentrated to200 mL, and hexanes (about 300 mL) was added. Crystallization beganspontaneously, and was allowed to continue at -5° C. for about 16 hours.The crystals were recovered by filtration, washed sparingly with 50%ethyl acetate-hexanes, and dried by suction to a constant weight (105.78g, 0.428 mol, 60.0% of theoretical). Recrystallization from refluxingethyl acetate (200 mL) provided the title compound as white crystals(93.85 g, 0.3795 mol, 53.2% of theoretical); m.p. 115.8°-117°; ¹ H-NMR(DMSO-d₆)δ: 6.71 (br d, J=7.4 Hz, 1H, NH), 4.52 (t, J=5.2 Hz, 1H, CH₂OH), 4.43 (d, J=5.1 Hz, 1H, CHOH), 4.31 (d, J=4.9 Hz, 1H, CHOH),3.54-3.41 (overlapping multiplet, 3H, CHN and CHOH), 3.34 (m,overlapping with HOD, w1/2=20Hz, CH₂ OH), 1.99 (dt, J=12.5, 6.8, 6.8 Hz,1H, HOCH₂ CH), 1.85 (br. m, w1/2=30 Hz, 1H, 1/2CH₂), 1.39 (s, 9H,C(CH₃)₃), 0.98 (dt, J=12.4, 7.8, 7.8 Hz, 1H, 1/2CH₂); [α]²⁰ ₅₈₉ -8.08°,[α]²⁰ ₅₇₈ -8.57°, [α]²⁰ ₅₄₆ -9.95°, [α]²⁰ ₄₃₆ -18.22, [α]²⁰ ₃₆₅ -29.36°(c=1.02, methanol); CI-MS (CH₄) 248(M+1).

Anal. Calcd. for C₁₁ H₂₁ O₅ N: C, 53.43; H, 8.56; N, 5.66. Found: C,53.45; H 8.58; N, 5.69.

A sample of the (-)-(2R, 3S)-isomer (25.60 g) was obtained from themother liquors by fractional crystallization from ethyl acetate; m.p.106°-107.2° C.; ¹ H-NMR (DMSO-d₆)δ: 5.93 (br d, J=7.6 Hz, 1H, NH), 4.77(d, J=4.9 Hz, 1H, CHOH), 4.58 (d, J=4.1 Hz, 1H, CHOH), 4.35 (br t,w1/2=15 Hz, 1H, CH₂ OH), 3.89 (br s, w1/2=10 Hz, 1H, OCH), 3.73 (br s,2H, OCH, NCH), 3.50 (br m, w1/2=20 Hz, 1H, 1/2OCH₂), 3.38 (br m,obscured by HOD, 1/2OCH₂), 1.90 (m, w 1/2=24 Hz, 2H, OCH₂ CH, 1/2CH₂),1.38 (s, 9H, C(CH₃)₃), 1.27 (m, 1H, 1/2CH₂); [ α]²⁰ ₅₈₉ -7.92°, [α]²⁰₅₇₈ -8.14°, [α]²⁰ ₅₄₆ -9.05°, [α]²⁰ ₄₃₆ -14.81°, [α]²⁰ ₃₆₅ -21.19°(c=1.36, methanol); CI-MS (CH₄), 248(M+1).

Anal. Calcd. for C₁₁ H₂₁ O₅ N, 0.05 H₂ O: C, 53.23; H, 8.57; N, 5.64.Found: C, 53.20; H, 8.55; N, 5.61.

In the same manner the racemate of Example 28 was converted to theracemate of title compound; m.p. 134°-136° C. (from ethyl acetate), 51%.¹ H-NMR identical with that of (-)-enantiomer.

Example 26 (±)-cis-4-Amino-2-cyclopentene-1-carboxylic acid,4-toluenesulfonate

A 500 mL, three-neck flask with vertical joints was charged with(±)-2-azabicyclo [2.2.1]hept-5-en-3-one (48.66 g, 0.4459 mol,Cambridge), and equipped with a mechanical stirrer, thermometer with gasinlet adapter connected to the nitrogen supply, and a powder funnel.Tetrahydrofuran (200 mL, reagent grade) was added, and the stirrerstarted in order to dissolve the solid. An endotherm of 13° C. wasnoted. A gentle nitrogen sweep was applied from the inlet adapter outthe powder funnel and 4-toluene sulfonic acid hydrate (93.52 g, 0.416mol, 1.1 equv) was added, along with a small amount of the titlecompound as seed. The powder funnel was replaced by a reflux condenser,and the flask was immersed in an oil bath preequilibrated to 35° C.Within 10 minutes, crystallization began, followed by an exothermpeaking at 60° C. in another 15 minutes. After the exotherm peaked, thebath was reset to 60°-65° C., and the reaction mixture was heated twohours at 60°-65° C. (internal), until a TLC of the supernatant liquid(silica, ethyl acetate eluent, iodine visualization) shows the absenceof starting lactam against an authentic spot. The mixture was thencooled in an ice bath to 5° C. A glass tube with a fritted end wasconnected via flexible tubing to a filter flask, in turn connected to avacuum source. The condenser was removed from the flask containing theslurry, the stirrer was stopped, and with a nitrogen sweep from the gasinlet, the flitted end of the stick was pushed to the bottom of theflask under the agitator. Vacuum was applied until the liquid wascompletely removed, the solids were reslurried in dry tetrahydrofuran(100 mL), and the filtration operation was repeated. The resulting whitesolids were reslurried in dry tetrahydrofuran (200 mL), and the openneck was capped with a septum. The resulting slurry of the titlecompound was used directly in the following Example; an analyticalsample was prepared similarly, except that it was dried first by suctionthen by the application of vacuum; m.p. 191°-193° C.; ¹ H-NMR (DMSO-d₆),δ: 12.62 (br s, 1H, CO₂ H), 7.93 (br s, 3H, NH₃ ⁺), 7.47 and 7.11 (dd,8.0 Hz, 2H each, Ar-H), 6.11 (dt, J=5.7, 1.9, 1.9, Hz, 1H, vinyl), 5.82(dt, J=5.7, 2.8, 2.8 Hz, 1H vinyl), 4.20 (br m, w1/2=21Hz, 1H, allylicH), 3.61 (br tt?, w1/2=21Hz, 1H, allylic), 2.29 (s, 3H, CH₃), 2.50 (dt?,J=5.8, 5.8, 11.5 Hz, (overlapping DMSO peak), 1/2CH₂), 1.92 (dt, J=6.7,6.7, 13.4 Hz, 1H, 1/2CH₂).

Anal. Calcd. for C₁₃ H₁₇ O₅ N₅ : C, 52.16; H, 5.72; N, 4.68; S, 10.71.Found: C, 52.16; H, 5.76; N, 4.66; S, 10.62.

Example 27 (±)-cis-4-Amino-2-cyclopentene-1-methanol

A dry, 2 L, three-neck flask was equipped with a mechanical stirrer,thermometer with gas inlet adapter connected to the nitrogen supply, andseptum. The flask was purged with nitrogen, immersed in an ice-acetonebath, and lithium aluminum hydride solution in tetrahydrofuran (1.0molar, 800 mL, 0.80 mol, Aldrich) was added via cannula. Drytetrahydrofuran (2×15 mL) was used to rinse in the lithium aluminumhydride solution. When the solution had cooled to 0° C., the slurry of(±)-cis-4-amino-2-cyclopentene-1-carboxylic acid 4-toluenesulfonate saltin tetrahydrofuran prepared in the previous Example was cannulated inwith good stirring, at such a rate as to keep the temperature less than10° C. and moderate the hydrogen evolution (about one hour). The flaskwas rinsed with dry tetrahydrofuran (2×15 mL), and the septum wasreplaced with a reflux condenser. The resulting clear, light ambersolution was slowly warmed to a gentle reflux over the course of twohours, at which point it became cloudy. After refluxing overnight (16hours), the heating bath was dropped, sodium fluoride (136.3 g, 3.25mol, reagent grade powder) was added, and the condenser reset fordownward distillation. The mixture was distilled to a thin slurry (700mL of distillate collected), then cooled in an ice bath. Diethyl ether(dry, 500 mL) was added, and the condenser was replaced by an additionfunnel containing water (43 mL, 2.4 mol). The water was added veryslowly (two hours), with care taken to control the rate of hydrogenevolution and maintain the temperature at 10 ±5° C. Meanwhile, water (54mL) was added to the above recovered distillate, and sufficientadditional tetrahydrofuran was added to bring the total volume to 900 mL(6% H₂ O). The reaction mixture was filtered by suction, and the cakedisplace-washed with tetrahydrofuran (100 mL). Part of the 6%water-tetrahydrofuran solution (300 mL) was used to slurry-wash thecake, which was then returned to the reaction flask. The cake wastriturated (25 minutes) in 6% water-tetrahydrofuran (400 mL), filtered,and displace-washed with 6% water-tetrahydrofuran (200 mL). The combinedfiltrates were concentrated to a pale yellow oil under vacuum (44.07 g,67.8% by HPLC, see Example 3). This oil, containing pure title compound,water, and a trace of tosylate salt, darkens rapidly under ambientconditions. It was immediately reacted to form the N-BOC derivative, astable, crystalline solid, (see the following Example). The filter cakewas returned to the flask and triturated in methanol (800 mL) for 48hours. The resulting slurry was filtered under a rubber dam, and thecake was washed with methanol (200 mL). The filtrate was concentratedunder vacuum to a yellow solid (56.80 g, 20.9% yield by HPLC; totaloverall yield 88.7%). This extract was also taken to the N-BOCderivative (see the following Example).

Example 28 (±)-cis-tert-ButylN-[4-(hydroxymethyl)-2-cyclopenten-1-yl]carbamate

The first extract of the previous example containing(±)-cis-4-Amino-2-cyclopentene-1-methanol (0.4459 mol) was dissolved in2:1 1,4-dioxane-water (1.2 L). Sodium bicarbonate (48.69 g, 0.580 mol)was added, the mixture was cooled in an ice-water bath anddi-tert-butyldicarbonate (110.25 g, 0.490 mol, Aldrich 97%) was added inone portion with rapid stirring. The resulting mixture was warmed toroom temperature over the course of one hour, then was concentratedunder vacuum to a volume of about 400 mL. The slurry was taken up inchloroform (300 mL), the phases were separated, and the aqueous (upper)phase was reextracted with chloroform (five portions of 300 mL each)until no product was observed in the extract by TLC (silica, 10%methanol-chloroform, iodine visualization, Rf=0.51). The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder vacuum to give the title compound as an oil. The final extract ofthe previous example was reacted similarly, and the crude title compoundthus obtained was combined with the above portion, the combined materialwas taken up in hexanes and evaporated under vacuum to remove residualchloroform. The oil then crystallized spontaneously. It was trituratedin cold hexanes and filtered to give the crude title compound as acrystalline solid, which was dried by suction to a constant weight(79.98 g, 0.3750 mol). Recrystallization from boiling ethyl acetate (70mL) and hexanes (300 mL) gave the title compound as a off-white,crystalline solid (73.43 g, 0.3443 mol); m.p. 54°-55.5° C.; ¹ H-NMR(DMSO-d₆)δ: 6.72 (d, J=7.9 Hz, 1H, NH), 5.80 and 5.60 (two m, 2H,CH═CH), 4.59 (t, J=5.2 Hz, 1H, OH), 4.45 (m, 1H, CHN), 3.35 (m,overlapping H₂ O, CH₂ O), 2.60 (m, 1H, CH), 2.30 (m, 1H, 1/2CH₂), 1.40(s, 9H, C(CH₃)₃), 1.2 (m, 1H, 1/2CH₂).

Anal. Calcd. for C₁₁ H₁₉ NO₃ : C, 61.94; H, 8.98; N, 6.57. Found: C,62.00; H, 8.99; N, 6.55.

The mother liquors were combined, chromatographed on silica gel (700 g,30% ethyl acetate-hexanes and 5% methanol-chloroform), and crystallizedas above to give a second portion of the title compound (10.49 g, 0.0492mmol). The total yield was thus 0.3935 mol, or 88.9% of theoretical fromthe starting (±)-2-azabicyclo [2.2.1]hept-5-en-3-one (corrected foraliquots taken).

Example 29 (±)-cis-4-Amino-2-cyclopentene-1-methanol

By the method of Examples 26 and 27, but on about twice the scale (97.40g, 0.8924 mol of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one) the titlecompound was obtained as extracts containing the title compound (0.7926mol, 88.8% of theoretical, allowing for aliquots removed, as determinedby the method of Example 23).

Example 30 (±)-cis-tert-ButylN-(4-[hydroxymethyl)-2-cyclopenten-1-yl]carbamate

The combined tetrahydrofuran extracts from the preceding Example wereconcentrated under vacuum to 1031 g, cooled in an ice-water bath, and amixture of sodium bicarbonate (97.46 g, 1.16 mol) in water (500 mL) wasadded. This was followed by di-tert-butyl dicarbonate (204.5 g), 0.9501mol). The mixture was stirred at 5° C. for two days. The methanolextracts from the preceding Example were evaporated to an oily solid(136.64 g), which was added to the mixture. After warming to roomtemperature, the organic solvents were evaporated under vacuum, and theresulting slurry was extracted with hexanes, three portions of methylenechloride, then hexanes again (200 mL each). The organic extracts wereevaporated to an oil, which was crystallized from hexanes (about 300mL), giving the title compound (154.15 g, 0.7229 mol), identical to theproduct of Example 28. Additional product was obtained by chromatographyof the mother liquors (10.5 g, 0.0491 mol, 86.6% of theoretical from thestarting lactam, allowing for aliquots removed).

Example 31 (±)-cis-4-Amino-2-cyclopentene-1-carboxylic acid,methanesulfonate

Beginning with (±)-2-azabicyclo[2.2.1]hept-5-en-3-one (5.111 g, 46.83mmol, Cambridge), by the method of Example 31, was prepared the titlecompound (10.268 g, 45.99 mmol, 98.2%); m.p. 137°-139° C.; ¹ H-NMR(DMSO-d₆)δ: 12.6 (br s, 1H, CO₂ H), 8.04 (br s, 3H, NH₃ ⁺), 6.10 (dt,J=5.6, 2.0, 2.0 Hz, 1H, vinyl), 5.85 (dt, J=5.3, 2.3, 2.3 Hz, 1H,vinyl), 4.19 (br s., w1/2=20 Hz, 1H, allylic H), 3.61 (m, w1/2=22 Hz,1H, allylic H). 2.53 (quintet, J=5.3 Hz (overlapping with DMSO peak),1/2CH₂), 2.39 (s, 3H, CH₃ SO₃ H), 1.93 (dt, J=6.7, 6.7, 13.7 Hz, 1H,1/2CH₂); CI-MS (CH₄): 128 (M+1); EI-MS: 127(M).

Anal. Calcd. for C₇ H₁₃ NO₅ S: C, 37.66; H, 5.87; N, 6.27; S, 14.36Found: C, 37.60; H, 5.85; N, 6.25; S, 14.30

Example 32 (±)-Cis-4-Amino-2-cyclopentene-1-carboxylic acid,4-toluenesulfonate

To a solution containing a catalytic amount of 4-toluene sulfonic acid(10 mg) in 30% aqueous hydrogen peroxide (0.30 mL, 2.7 mmol) was added3-tosyl-2-azabicyclo [2.2.1]hepta-2,5-diene (369 mg, 1.49 mmol),prepared by the method of J. C. Jagt and A. M van Leusen, J. Org. Chem.1974, 39, 564-566, in portions, with rapid stirring. A large exotherm isnoted, stabilizing at 75° C. during the last half of the addition. Afterstirring 70° C. for 40 minutes, the mixture was repeatedly diluted withwater (6 mL total) and filtered until a clear solution resulted. Thesolution was evaporated to an oil which crystallized (349 mg). This wastriturated in tetrahydrofuran, filtered, and dried under vacuum to givethe title compound (202 mg, 45.2% of theoretical), ¹ H-NMR spectrumidentical to the product of Example 26.

Example 33(±)-cis-[4-(4,5-Dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol

(±)-cis-tert-Butyl N-[4-(hydroxymethyl)-2-cyclopenten-1-yl]carbamate(50.0 g, 0.230 mole) was stirred in 25% trifluoroacetic acid inmethylene chloride (1.5 L) at 0° C. for 1.0 hour. Evaporation ofvolatiles left the trifluroacetic acid salt of the amine described inExample 27 as a dark oil. To this oil were added t-butanol (350 mL),potassium carbonate (65 g), and 1,2,4-trichloro-5-nitrobenzene (Aldrich,54.7 g, 0.230 mole as 97%). The resulting mixture was refluxed withvigorous stirring for 3 days. Volatiles were removed under vacuum andthe residue triturated with methanol. The methanol-soluble material waschromatographed on silica gel. Crude product was eluted with 2%methanol-chloroform to give orange solid (38.0 g). Crystallization fromethyl acetate-hexanes gave title compound as orange crystals (34.0 g,49%), m.p. 96°-98° C.; ¹ H-NMR(DMSO-d₆) and mass spectrum(CI) consistentwith structure and identical with samples of chiral enantiomersdescribed in Examples 53 and 64.

Anal. Calcd. for C₁₂ H₁₂ N₂ Cl₂ O₃ : C, 47.55; H, 3.99: N, 9.24 Cl,23.39. Found: C, 47.75; H, 4.10; N, 9.20; Cl, 23.52.

Continued elution of the column gave further fractions containing titlecompound with minor low R_(f) impurities. These fractions were combinedwith the mother liquor from the above crystallization and recrystallizedfrom ethyl acetate-hexanes to give additional orange solid (16.7 g)having identical ¹ H-NMR spectrum and bringing the total yield to 73%.

Example 34(±)-cis-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol

(±)-cis-[4-(4,5-Dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol(5.00 g, 16.5 mmol) in ethanol (100 mL)-water (35 mL) was heated whileiron powder (325 mesh, 99.9%, Aldrich, 9.2 g, 0.165 equiv) and iron(II)sulfate heptahydrate (Aldrich, 98+%, 2.3 g, 8.2 mequiv) were added. Themixture was refluxed 1.75 hours. Solids were filtered off and theethanol filtrate-wash concentrated to an oil. Triethylorthoformate (75mL) and methanesulfonic acid (0.05 mL) were added to the oil and theresulting solution stirred at ambient temperature for 18 hours.Concentration in vacuo left an oil which was redissolved in 1Nhydrochloric acid (25 mL)-dioxane(5 mL). After 3 hours, the pH wasadjusted to 7 with 1N sodium hydroxide and the solution extracted withchloroform (3×50 mL). The contents of the dried (sodium sulfate)chloroform solution was chromatographed on silica gel. Title compoundwas eluted with 5% methanol-chloroform and crystallized from ethylacetate-hexanes to give white crystals (3.85 g, 82%), m.p. 166°-169° C.;¹ H-NMR(DMSO-d₆) and mass spectrum(CI) consistent with structure.

Anal. Calcd. for C₁₃ H₁₂ N₂ Cl₂ O: C, 55.14; H, 4.27: N, 9.89; Cl,25.04. Found: C, 55.20; H, 4.32; N, 9.84; Cl, 24.94.

Example 35(±)-cis-[4-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol

(±)-cis-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol(1.55 g, 5.47 mmol) was acetylated in pyridine (17 mL) with aceticanhydride (0.6 mL) at ambient temperature for 2 days. Volatiles wereremoved in vacuo and the residual oil partitioned between chloroform andaqueous sodium bicarbonate. The chloroform solution was dried (sodiumsulfate) and concentrated to dryness. The residue was dissolved in drydioxane (10 mL) and the solution brought to reflux. N-bromosuccinimide(930 mg, 5.23 mmol) was added all at once. The dark solution was cooledafter 4 minutes of reflux. Volatiles were evaporated in vacuo and theresidue was chromatographed on silica gel. Elution with 2-5%methanol-chloroform gave fractions containing starting material (1.05 g)followed by fractions containing title compound as a dark oil (0.28 g).The recovered starting material was again treated withN-bromosuccinimide and the crude product chromatographed. Allproduct-containing fractions were combined and rechromatographed onsilica gel with elution by hexanes-ethyl acetate to give the acetate oftitle compound as a yellow oil (0.62 g). Deacetylation was carried outas in Example 4. Volatiles were evaporated in vacuo from the neutralizedsolution and the residue was chromatographed on silica gel. Elution with2% methanol-chloroform gave(±)-cis-[4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanolas off-white powder (293 mg, 15%), after resolidification fromhexanes-ethyl acetate, m.p. 126°-128.5° C.; ¹ H-NMR(DMSO-d₆)δ: 8.09 and7.95 (both s, 1 each, aromatic CH), 6.24-6.20 and 5.98-5.94 (both m, 2,CH═CH), 5.81-5.76 (2 m, 1 each, CH₂ O), 4.96 (t, J=4.9 Hz, 1, OH),3.02-2.95 (m, 1, CH), 2.67-2.51 (m overlapping solvent, 1/2CH₂), 2.0-1.8(m, 1, 1/2CH₂); mass spectrum (CI) consistent with structure.

Anal. Calcd. for C₁₃ H₁₁ N₂ BrCl₂ O: C, 43.13; H, 3.06; N, 7.74; totalhalogen as Cl, 29.38. Found: C, 43.20; H, 3.07; N, 7.71; total halogenas Cl, 29.35.

Example 36(±)-cis-3-(5,6-Dichloro-1H-benzimidazol-1-yl)-1-cyclopentanemethanol

A mixture of(±)-cis-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol(5.00 g, 16.5 mmol) and Raney nickel (Aldrich, slurry in water, 500 mgwet) in n-propanol (250 mL) was shaken under hydrogen (50 psi) on a Parrshaker for 2 hours. The catalyst was filtered off, solvent evaporated invacuo, and the residue dissolved in triethylorthoformate(300mL)-methanesulfonic acid (200 mg). After 18 hours, the solution wasconcentrated to a syrup which was dissolved in 1N hydrochloric acid (40mL) and stirred at ambient temperature overnight. The pH was adjusted to7 with 1N sodium hydroxide and the solution extracted with chloroform(3×50 mL). The contents of the dried (sodium sulfate) chloroformsolution was chromatographed on silica gel. Title compound was elutedwith 5% methanol-chloroform as a colorless oil which solidified fromethyl acetate-hexanes to give white powder (3.98 g, 85%). m.p. 142°-145°C.; ¹ H-NMR(DMSO-d₆) and mass spectrum(CI) consistent with structure.

Anal. Calcd. for C₁₃ H₁₄ N₂ Cl₂ O: C, 54.75; H, 4.95: N, 9.82; Cl,24.86. Found: C, 54.88; H, 4.99; N, 9.70; Cl, 24.74.

Example 37(±)-cis-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1-cyclopentanemethanol

(±)-cis-3-(5,6-Dichloro-1H-benzimidazol-1-yl)-1-cyclopentanemethanol(3.65 g, 12.8 mmol) was acetylated in pyridine (40 mL)-acetic anhydride(2 mL) at ambient temperature overnight. Volatiles were evaporated andthe residue partitioned between chloroform and saturated aqueous sodiumcarbonate. The chloroform layer was dried (sodium sulfate) andevaporated to a glass which was reacted with N-bromosuccinimide as inExample 3. The crude bromination product was chromatographed on silicagel and the acetate of title compound was eluted with 5%methanol-chloroform as an off-white powder (2.8 g, 55%); ¹H-NMR(DMSO-d₆) and mass spectrum(CI) consistent with structure. Thispowder (2.00 g, 4.92 mmol) was deacetylated as in Example 4 to givecolorless solid foam, after elution from a silica gel column with 2-3%methanol-chloroform. Crystallization from ethyl acetate-hexanes gave(±)-cis-3-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1-cyclopentanemethanolas off-white crystals (1.08 g, 60%), m.p. 111°-112° C.; ¹H-NMR(DMSO-d₆)δ: 8.08 and 7.96 (both s, 1 each, 2 aromatic CH),5.06-5.01 (m, 1, NCH), 4.79 (t, J=5.1 Hz, 1,)H), 3.56-3.51 (m, 2, CH₂OH), 2.28-2.05 (m, 5, 2 CH₂ and CH); mass spectrum(CI): 367(54),365(100), 363(71, M+1).

Anal. Calcd. for C₁₃ H₁₃ N₂ BrCl₂ O: C, 42.89; H, 3.60: N, 7.69; totalhalogen as Br, 65.84, as Cl, 29.21. Found: C, 42.94; H, 3.63; N, 7.62;total halogen as Br, 65.75, as Cl, 29.17.

Example 38 (±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate and (±)(1R*, 2S*, 3R*,5R*)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate

To a solution of(±)-cis-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol(20.0 g, 66.0 mmol) and N-methylmorpholine N-oxide (Aldrich, 60% aqueoussolution, 12.0 mL, 69 mmol) in acetone (280 mL) was added osmiumtetroxide (2.5% in t-butyl alcohol, Aldrich, 1.24 mL). After stirring atambient temperature for 18 hours, volatiles were removed in vacuo andthe residue stirred with pyridine (200 mL)-acetic anhydride (40 mL) foran additional 18 hours. The solution was concentrated to a thick red oilwhich was partitioned between saturated aqueous sodium carbonate andchloroform. The chloroform layer was dried (sodium sulfate) and thenconcentrated to an oil in vacuo. A mixture of the isomeric titlecompounds was eluted from a silica gel column with 2%methanol-chloroform and crystallized from ethyl acetate-hexanes (withseeding by crystals of the (1R*,2S*)-isomer prepared by the method ofExample 1) to give (±)-(1R*, 2S*, 3S*,5S*)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate as orange crystals (17.4 g, 57%), m.p. 154°-156° C.; ¹H-NMR(DMSO-d₆) identical to that of the sample described in Example 1.

Continued crystallization of the mother liquor contents from ethylacetate-hexanes gave (±)(1R*, 2S*, 3R*,5R*)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate as orange crystals (8.82 g, 29%), m.p. 105°-107° C.; ¹H-NMR(DMSO-d₆) identical with that of the chiral sample described inExample 61.

Anal. Calcd. for C₁₈ H₂₀ N₂ Cl₂ O₈ : C, 46.67; H, 4.35; N, 6.05; Cl,15.31. Found: C, 46.50; H, 4.33; N, 5.96; Cl, 15.23.

Example 39 (±)(1R*, 2S*, 3R*,5R*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)(1R*, 2S*, 3R*,5R*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate (5.00 g, 10.8 mmol) was stirred in ammonia/methanol (ca. 2N,100 mL) at ambient temperature for 18 hours. Evaporation of volatiles invacuo left residual orange solid (±)-(1R*, 2S*, 3R*,5R*)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediolhaving an identical R_(f) on silica gel TLC plates to that of the chiralsample described in Example 54. This solid was reduced with Raneynickel/hydrogen(45 psi) in isopropanol (200 mL). Catalyst was filteredoff with Celite. The filtrate-wash was evaporated to dryness in vacuo.The residue was refluxed in formic acid (96%, 50 mL) for one hour, asdescribed in Example 2. The oil remaining on evaporation of the formicacid was dissolved in methanol. The pH was adjusted to 13 with aqueous5N sodium hydroxide and the solution was stirred at ambient temperaturefor one hour to hydrolyze formate esters. The pH was adjusted to 7 with1N hydrochloric acid and volatiles removed by evaporation in vacuo.Pyridine (100 mL) and acetic anhydride (4 mL) were added to the residueand the mixture stirred at ambient temperature overnight. Evaporation ofvolatiles in vacuo followed by chromatography on silica gel with 1%methanol-chloroform gave (±)(1R*, 2S*, 3R*,5R*)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate as white crystals from ethanol-water (2.6 g, 53%), ¹H-NMR(DMSO-d₆) consistent with structure.

(±)(1R*, 2S*, 3R*,5R*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (2.5 g, 5.7 mmol) was dissolved in dry dioxane (15 mL) and thesolution refluxed while freshly recrystallized N-bromosuccinimide (2.10g, 11.5 mmol) was added all at once. After 5 minutes of reflux, thered-brown solution was evaporated in vacuo to a red oil. A chloroformsolution of this oil was washed with water and then dried (sodiumsulfate). The chloroform solution was concentrated to an oil which waschromatographed on silica gel. Product-containing fractions were elutedwith 2-4% methanol-chloroform. Crystallization from ethylacetate-hexanes gave as off-white solid (1.5 g, 50%); ¹H-NMR(DMSO-d₆)consistent with structure of title compound. Such a samplewas rechromatographed on silica gel with elution by chloroform to give(±)(1R*, 2S*, 3R*,5R*)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate as white crystals, after crystallization from ethylacetate-hexanes, m.p. 166° -167° C.; ¹ H-NMR(DMSO-d₆)δ: 8.14 and 7.96(both s, 1 each, 2 aromatic CH), 5.6-5.35 (m, 3, 2 OCH and NCH), 4.4-4.1(m, 2, OCH₂), 2.8-2.4 (m overlapping solvent, 2 CH), 2.4-2.1 (moverlapping s at 2.25, total 4, CH and CH₃), 2.04 (s, 3, CH₃), 1.37 (s,1, CH₃); mass spectrum(CI): 525(53), 523(100), 521(54, M+1).

Anal. Calcd for C₁₉ H₁₉ N₂ BrCl₂ O₆ : C, 43.70; H, 3.67; N, 5.37; totalhalogen as Cl, 20.37. Found: C, 43.65; H, 3.68; N, 5.35; total halogenas Cl, 20.32.

Example 40 (±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (4.20 g, 9.48 mmol) was refluxed in dry dioxane (25 mL) whilefreshly recrystallized N-bromosuccinimide (3.37 g, 18.9 mmol) was addedall at once. After 5 minutes of reflux, volatiles were removed in vacuo.The residue was partitioned between water and chloroform. The chloroformlayer was dried (sodium sulfate), and evaporated to an oil which waschromatographed on silica gel with elution by 1:1 hexanes-ethyl acetate.Resolidification from ethanol-water gave title compound as white powder(3.10 g, 63%), m.p. 157°-158.5° C.; ¹ H-NMR(DMSO-d₆) identical to thatof the sample described in Example 3.

Anal. Calcd. for C₁₉ H₁₉ N₂ BrCl₂ O₆ : C, 43.71; H, 3.67: N, 5.37; totalhalogen as Cl, 20.37. Found: C, 43.66; H, 3.72; N, 5.34; total halogenas Cl, 20.32.

Example 41 (±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-amino-4,5-dichloroanilino)-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate (4.30 g, 9.28 mmol) in isopropanol (250 mL) was shaken withRaney nickel (Aldrich, slurry in water, 400 mg wet) under hydrogen (50psi) on a Parr shaker for 2.75 hours. Catalyst was filtered off withCelite and the filtrate-wash (350 mL) stored at -5° C. Yellow crystalsof title compound formed slowly (2.35 g, 58%), m.p. 124°-125° C.; ¹H-NMR(DMSO-d₆)δ: 6.70 and 6.57 (both s, 1 each, 2 aromatic CH), 5.15-4.9(m, 5, NH₂, NH, and 2 OCH), 4.2-4.0 (m, 2, CH₂ O), 3.9-3.75 (m, 1, NCH),2.5-2.4 (m overlapping solvent, CH₂), 2.07, 2.04, and 2.01 (all s, 9, 3CH₃), 1.4-1.2 (m, 1, CH); mass spectrum(CI): 433(M+1).

Anal. Calcd. for C₁₈ H₂₂ N₂ Cl₂ O₆ : C, 49.90; H, 5.12; N, 6.47; Cl,16.37. Found: C, 50.00; H, 5.13; N, 6.38; Cl, 16.28.

Concentration of the mother liquor gave additional title compound asyellow powder (1.00 g, 25%) with sufficient purity for use (Example 44).

Example 42 (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-Dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate (1.00 g, 2.16 mmol), Raney nickel (Aldrich, slurry in water,100 mg wet), and isopropanol (200 mL) were shaken under hydrogen (50psi) for 1.25 hours. Catalyst was filtered off with Celite and thefiltrate-wash evaporated to dryness. The residual yellow oil wasdissolved in triethylorthoaceate (20 mL) with 1 drop of methanesulfonicacid and the solution stirred at ambient temperature for 18 hours.Volatiles were removed in vacuo and the residue stirred in dioxane (20mL)-1N sodium hydroxide (10 mL) for 5 hours at ambient temperature. ThepH was then adjusted to 1 with concentrated hydrochloric acid andstirring continued for 15 minutes, at which point TLC (silica gel,developed with 20% methanol-chloroform) showed one UV-absorbing spot atR_(f) 0.25. The solution was neutralized with sodium hydroxide andvolatiles evaporated in vacuo. The residue was chromatographed on asilica gel column and title compound eluted with 10-15%methanol-chloroform. Crystallization from ethanol-methanol-water gave(±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolas fine white crystals (0.482 g, 67%), m.p. 222°-226° C.; .sup. 1H-NMR(DMSO-d₆)δ: 8.30 and 7.72 (both s, 2, 2 aromatic CH), 5.0-4.8 (m,3, 2 OH and NCH), 4.56 (t, J=5.1 Hz, 1, CH₂ OH), 4.2-4.1 (m, 2, 2 OCH),3.8-3.5 (m, 2, CH₂ O), 2.58 (s, 3, CH₃), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m,2, CH₂); mass spectrum (CI): 332 (M +1).

Anal. Calcd. for C₁₄ H₁₆ N₂ Cl₂ O₃ : C, 50.78; H, 4.87; N, 8.46; Cl,21.24. Found: C, 50.72; H, 4.91; N, 8.54; Cl, 21.13.

Example 43 (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-Dichloro-2-ethyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

In the same manner as Example 42, (±)-(1R*, 2S*, 3S*,5S*)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate (1.00 g, 2.16 mmol) was converted to title compound usingtriethylorthopropionate (Aldrich, 97%, 22 mL) for the benzimidazoleformation. Solidification from ethanol-water gave (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolas white powder (0.463 g, 63%), m.p. 191°-193° C.; ¹ H-NMR(DMSO-d₆)δ:8.10 and 7.86 (both s, 2, 2 aromatic CH), 5.10 (t, J=4.7 Hz, 1, OH),4.94 (d, J=6.9 Hz, 1, OH), 4.8-4.6 (m overlapping d at 4.71, J=3.9 Hz,total 2, NCH and OH), 4.5-4.3 (m, 1, OCH), 3.9-3.8 (m, 1, OCH),3.75-3.45 (m, 2, OCH₂), 2.93 (q, J=7.4 Hz, 2, CH₂ CH₃), 2.2-2.0 (m, 3,CH₂ and CH), 1.34 (t, J=7.4 Hz, 3, CH₃ ); mass spectrum (CI): 345 (M+1).

Anal. Calcd. for C₁₅ H₁₈ N₂ Cl₂ O₃.0.25 H₂ O: C, 51.52; H, 5.33; N,8.01; Cl, 20.27. Found: C, 51.59; H, 5.31; N, 8.05; Cl, 20.19.

Example 44 (±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-amino-4,5-dichloroanilino)-1,2-cyclopentanediyldiacetate (2.25 g, 5.19 mmol), 1,1'-thiocarbonyldiimidazole (Aldrich,1.03 g, 5.19 mmol as 90%), and toluene (125 mL) were refluxed for 30minutes. Additional 1,1'-thiocarbonyldiimidazole (0.51 g) was added andreflux continued for an additional 15 minutes. Volatiles were evaporatedin vacuo and the residual yellow oil dissolved in chloroform (75 mL) andwashed with water (2×25 mL). The chloroform layer was dried (sodiumsulfate) and concentrated in vacuo to a yellow oil. Crystallization fromethyl acetate-hexanes gave tan crystals (2.30 g, 93%) with ¹ NMRidentical to that described below. Such a sample was further purified byelution from a silica gel column with 4% methanol-chloroform beforecrystallization from ethyl acetate-hexanes to give (±)-(1R*, 2S*, 3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate as off-white crystals, m.p. 208°-209° C.;1H-NMR(DMSO-d₆)δ: 13.2 (br s, 1, NH), 8.05 and 7.39 (both s, 2, 2aromatic CH), 6.0-5.8 (m, 1, OCH), 5.6-5.3 (m, 2, OCH and NCH),4.40-4.15 (m, 2, OCH₂), 2.6-2.5 (m overlapping solvent, CH), 2.4-2.0 (moverlapping two s at 2.09 and 2.06, total 8, CH₂ and 2 CH₃), 1.93 (s, 3,CH₃); mass spectrum(CI): 475 (M+1).

Anal. Calcd. for C₁₉ H₂₀ N₂ Cl₂ O₆ S: C, 48.01; H, 4.24; N, 5.89; Cl,14.92; S, 6.75. Found C, 48.11; H, 4.22; N, 5.90; Cl, 14.85; S, 6.74.

Example 45 (±)-(1R*, 2S*, 3S*,5S*)-5-[2-(Benzylthio)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

A mixture of (±)-(1R*, 2S*, 3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (0.50 g, 1.05 mmol), benzyl bromide (0.3 mL, 2.5 mmol) andanhydrous potassium carbonate (0.145 g, 1.05 mequiv as 98%) in dioxane(5 mL) was stirred vigorously at ambient temperature for 2.5 days.Volatiles were evaporated in vacuo and the residue partitioned betweenchloroform and water. The chloroform layer was dried(sodium sulfate) andconcentrated to an oil which was stirred in ammonia-methanol (40 mL ofhalf-saturated) for 18 hours. Volatiles were evaporated and the residuesolidified from 3:1 methanol-water to give title compound as a whitepowder (300 mg, 65%), m.p. 160°-162° C.; ¹ H-NMR(DMSO-d₆)δ: 8.04 and7.89 (both s, 1 each, 2 aromatic CH), 7.5-7.2 (m, 5, C₆ H₅), 5.06 (t,J=4.7 Hz, 1, OH), 4.98 (d, J=6.2 Hz, 1, OH), 4.75-4.55 (m overlapping dat 4.68, J=3.7 Hz, and s at 4.63, total 4, NCH, OH, and SCH₂); massspectrum(CI): 439 (M+1).

Anal. Calcd. for C₂₀ H₂₀ N₂ Cl₂ O₃ S: C, 54.68; H, 4.59; N, 6.38; totalhalogen as Cl, 16.14; S, 7.30. Found: C, 54.75; H, 4.62; N, 6.38; totalhalogen as Cl, 16.21; S, 7.27.

Example 46 (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-Dichloro-2-methoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

Sodium (spheres, 0.10 g, 4.8 mequiv) were added to dry methanol (15 mL).(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (0.560 g, 0.958 mmol) was added to the sodium methoxide inmethanol and the solution stirred at ambient temperature under nitrogenfor 5 hours. The solution was then neutralized with 1N hydrochloric acidand volatiles removed in vacuo. The residual solid was chromatographedon silica gel. (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-Dichloro-2-methoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolwas eluted with 10% methanol-chloroform as a white powder, aftertrituration with diethyl ether (0.211 g, 64%), m.p. 204°-206° C. dec; ¹H-NMR(DMSO-d₆)δ: 7.82 and 7.67 (both s, 2, aromatic CH), 4.9 (m, 2,2OH), 4.7-4.6 (m overlapping d at 4.61, J=4.1 Hz, 2 total, NCH and OH),4.4-4.3 (m, 1, OCH), 4.11 (s, 3, OCH₃), 3.8 (m, 1, OCH), 3.6-3.4 (m, 2,OCH₂), 2.1-2.0 (m, 2, CH₂), 1.9-1.8 (m, 1, CH); mass spectrum (CI):347(M+1).

Anal. Calcd. for C₁₄ H₁₆ N₂ Cl₂ O₄ : C, 48.43; H, 4.65: N, 8.07; Cl,20.42. Found: C, 48.23; H, 4.71; N, 7.98; Cl, 20.51.

Example 47 (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-Dichloro-2-phenoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

Phenol (72 mg, 0.77 mmol) and anhydrous potassium carbonate (106 mg,0.77 mmol) were stirred in dry N,N-dimethylformamide (5 mL) undernitrogen for 1.0 hour. (±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (400 mg, 0.770 mmol) was added and the mixture stirred at 80°C. (oil bath) for 18 hours. Volatiles were removed in vacuo and theresidue partitioned between chloroform and water. The chloroform layerwas dried (sodium sulfate) and volatiles evaporated. The residual oilwas stirred in 4N ammonia in methanol (30 mL) at ambient temperature for18 hours. Evaporation and chromatography of the residue on silica gelwith elution by 2% methanol-chloroform gave (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-dichloro-2-phenoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolas white solid foam from ethyl acetate (215 mg, 68%); ¹ H-NMR(DMSO-d₆)δ:7.98 and 7.71 (both s, 2, aromatic CH), 7.6-7.3 (m, 5, C₆ H₅), 5.07 (d,J=6.4 Hz, 1, OH), 5.0-4.75 (m overlapping t at 4.95, J=3.1 Hz, total 2,NCH and OH), 4.71 (d, J=3.9 Hz, 1, OH), 4.5-4.35 (m, 1, OCH), 3.9-3.8(m, 1, OCH), 3.7-3.4 (m, 2, OCH₂), 2.3-1.9 (m, 3, CH₂ and CH); massspectrum (CI): 409 (M+1).

Anal. Calcd. for C₁₉ H₁₈ N₂ Cl₂ O₄ : C, 55.15; H, 4.51: N, 6.77; C,17.14. Found: C, 55.14; H, 4.52; N, 6.72; Cl, 17.07.

Example 48 (±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (5 mL)and cyclopropylamine (0.66 mL, 9.6 mmol) was added. The solution wasrefluxed under nitrogen for two hours. Additional cyclopropylamine (0.66mL) was added and reflux continued for an additional 18 hours. Thesolution was cooled and methanol saturated with ammonia at 0° C. (5 mL)was added. After two days at ambient temperature, volatiles were removedin vacuo and the residue chromatographed on silica gel. (±)-(1R*, 2S*,3S*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediolwas eluted with 7% methanol-chloroform and solidified from ethylacetate-hexanes to white powder (210 mg, 59%), m.p. 223°-224° C.; ¹H-NMR(DMSO-d₆)δ: 7.64 and 7.46 (both s, 2, aromatic CH), 7.11 (m, 1,NH), 5.11 (t, J=4.3 Hz, 1, OH), 4.77 (d, J=7.0 Hz, 1, OH), 4.67 (d,J=3.7 Hz, 1, OH), 4.65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m, 1, OCH),3.7-3.4 (m, 2, OCH₂), 2.85-2.70 (m, 1, NCH of cyclopropyl), 2.15-1.80(m, 3, CH₂ and CH of cyclopentane), 0.80-0.50 (m, 4, 2 CH₂ ofcyclopropyl); mass spectrum (CI): 372(M+1).

Anal. Calcd. for C₁₆ H₁₉ N₃ Cl₂ O₃ : C, 51.63; H, 5.15: N, 11.29; Cl,19.05. Found: C, 51.41; H, 5.20; N, 11.19; Cl, 19.16.

Example 49 (±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(dimethylamino)-1H-benzimidazol-1-yl]-3-hydroxymethyl)-1,2-cyclopentanediol

(±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (500 mg, 0.958 mmol) and 40% aqueous N,N,-dimethylamine (6.0mL) were refluxed for 2.5 hours. Volatiles were removed in vacuo and theresidue was solidified from 1:1 ethanol-water to give (±)-(1R*, 2S*,3S*,5S*)-5-[5,6-dichloro-2-(dimethylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediolas white powder (263 mg, 76%), m.p. 190°-193° C.; ¹ H-NMR(DMSO-d₆)δ:7.89 and 7.66 (both s, 2, aromatic CH), 5.07 (t, J=4.5 Hz, 1, OH), 4.97(d, J=5.9 Hz, 1, OH), 4.8-4.6 (m overlapping d at 4.62, J=3.5 Hz, total2, NCH and OH), 4.55-4.4 (m, 1, OCH), 3.9 -3.75 (m, 1 OCH), 3.7-3.4 (m,2, OCH₂), 2.92 (s, 6, 2 CH₃), 2.2-1.9 (m, 3, CH₂ and CH); mass spectrum(CI): 360(M+1).

Anal. Calcd. for C₁₅ H₁₉ N₃ Cl₂ O₃.0.65 H₂ O: C, 48.44; H, 5.50: N,11.30; Cl, 19.06. Found: C, 48.39; H, 5.31; N, 10.88; Cl, 19.49.

Example 50 (±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(cyclopentylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (500 mg, 0.958 mmol) and cyclopentylamine (0.95 mL, 9.6 mmol)were refluxed in absolute ethanol (5 mL) for 3.5 hours. Methanolicammonia (25 mL saturated at 0° C.) was added and stirring continued foran additional 18 hours. Volatiles were removed in vacuo and the residuechromatographed on silica gel. Elution with 6-8% methanol-chloroformfollowed by crystallization from ethyl acetate-hexanes gave (±)-(1R*,2S*, 3S*,5S*)-5-[5,6-dichloro-2-(cyclopentylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediolas white powder (155 mg, 41%), m.p. 270°-271° C. dec; ¹ H-NMR(DMSO-d₆)δ:7.58 and 7.37 (both s, 2, 2 aromatic CH), 6.67 (d, J=6.8 Hz, 1, NH),5.11 (t, J=4.5 Hz, 1, OH), 4.79 (d, J=7.4 Hz, 1, OH), 4.68 (d, J=3.7 Hz,1, OH), 4.6-4.5 (m, 1, NCH), 4.4-4.3 (m, 1, OCH), 4.2-4.1 (m, 1, NCH ofcyclopentylamino), 3.79-3.77 (m, 1, OCH), 3.75-3.5 (m, 2, OCH₂), 2.1-1.8(m, 5, 2CH₂ and CH), 1.7-1.3 (m, 6, 3 CH₂); mass spectrum(CI): 400(M+1).

Anal. Calcd. for C₁₈ H₂₃ N₃ Cl₂ O₃.0.10 EtOAc: C, 54.02; H, 5.86: N,10.27; Cl, 17.33. Found: C, 53.77; H, 5.83; N, 10.30; Cl, 17.52.

Example 51 (±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (500 mg, 1.13 mmol) was dissolved in dry N,N-dimethylformamide(4 mL) and heated to 95°-105° C. N-Iodosuccinimide (534 mg, 2.3 mmol as95%) was added in portions over 5.5 hours. Volatiles were removed invacuo and the residue chromatographed on silica gel. Elution with 10%ethyl acetate-hexanes followed by solidification from ethanol-water gave(±)(1R*, 2S* 3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate as a white powder (255 mg, 40%), m.p.152.5°-153° C.; ¹H-NMR(DMSO-d₆)δ: 8.32 and 7.94 (both s, 2, 2 aromatic CH), 5.8-5.7 (m,1, OCH), 5.4-5.3(m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.35-4.2 (m, 2, OCH₂),2.7-2.6 (m, 1, CH), 2.35-2.25 (m, 2, CH₂), 2.11, 2.08, and 1.93 (all s,3 each, 3 CH₃); mass spectrum(CI) 569 (M +1).

Anal. Calcd. for C₁₉ H₁₉ N₂ Cl₂ IO₆ : C, 40.10; H, 3.37; N, 4.92; totalhalogen as Cl, 18.69. Found: C, 40.27; H, 3.39; N, 4.88; total halogenas Cl, 18.63.

Example 52 (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-Dichloro-2-iodo-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

Sodium carbonate (40 mg, 0.37 mmol) was dissolved in water (0.7 mL) andmethanol (3 mL) and ethanol (3 mL) were added. To this stirred mixturewas added (±)(1R*, 2S*, 3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (215 mg, 0.37 mmol). After 2 hours at ambient temperature,acetic acid was added to adjust the pH to 7 and volatiles wereevaporated in vacuo. Resolidification of the residual solid from 3:1ethanol-water gave (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolas a white powder (153 mg, 94%), m.p. 209°-210° C. dec.; ¹H-NMR(DMSO-d₆)δ: 8.22 and 7.91 (both s, 2, 2 aromatic CH), 5.12 (t,J=4.5 Hz, 1, OH), 4.95 (d, J=6.2 Hz, 1, OH), 4.9-4.8 (m, 1, NCH), 4.70(t, J=3.5 Hz, 1, OH), 4.6-4.5 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.7-3.6and 3.55-3.45 (both m, 1 each, OCH₂), 2.2-2.0 (m, 3, CH₂ and CH); massspectrum(CI): 443 (M+1).

Anal. Calcd. for C₁₃ H₁₃ N₂ Cl₂ IO₂ : C, 35.24; H, 2.96; N, 6.32; totalhalogen as Cl, 24.01. Found: C, 35.30; H, 3.01; N, 6.23; total halogenas Cl, 23.95.

Example 53 (1S,4R)-[4-(4,5-Dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol

(-)-(1R, 4S)-tert-Butyl N-[4-hydroxymethyl)-2-cyclopenten-1-yl]carbamate(15.00 g, 70.3 mmol) was converted by the method of Example 33 to (1S,4R)-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol,isolated as a yellow powder after elution from a silica gel column with1:1 hexanes-chloroform and resolidification from ethyl acetate-hexanes(9.97 g, 47%), m.p. 94.5°-96.5° C.; ¹ H-NMR(DMSO-d₆)δ: 8.24 (s, 1,benzimidazole CH), 8.09 (d, J=8.1 Hz, 1, NH), 7.51 (s, 1, benzimidazoleCH), 5.95 and 5.85 (both m, 2, CH═CH), 4.9-4.7 (m overlapping t at 4.78,J=5.1 Hz, total 2, CHN and OH), 3.4 (m, 2, CH₂ O), 2.80 (m, 1, CH),2.6-2.4 (m overlapping solvent, CH), 1.5-1.4 (m, 1, CH); massspectrum(CI): 303 (M+1); [α]²⁰ ₅₈₉ +199°, [α]²⁰ ₅₇₈ +222°, [α]²⁰ ₅₄₆+333° (c=0.267, methanol).

Anal. Calcd. for C₁₂ H₁₂ N₂ Cl₂ O₃.0.18 C₆ H₁₄ : C, 49.30; H, 4.59; N,8.79; Cl, 22.25. Found: C, 49.64; H, 4.64; N, 8.68; Cl, 22.10.

Example 54 (1S, 2R, 3R,5R)-5-(4,5-Dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanedioland (1R, 2S, 3R,5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol

To a solution of (1S,4R)-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol (8.60g, 27.6 mmol) and N-methylmorpholine N-oxide (Aldrich, 60% aqueoussolution, 5.02 mL, 29.0 mmol) in acetone (90 mL) was added osmiumtetroxide (Aldrich, 2.5% in t-butyl alcohol, 0.51 mL). After stirring atambient temperature for 18 hours, an additional 0.25 mL of 60% aqueousN-methylmorpholine N-oxide was added and the solution stirred for anadditional 5 hours. Volatiles were evaporated in vacuo and the residuerecrystallized twice from 95% ethanol to give (1S, 2R, 3R,5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediolas yellow powder (1.78 g, 19%), m.p. 197°-199° C.; ¹ H-NMR(DMSO-d₆)δ:8.23 (s, 1, benzimidazole CH), 8.1 (d, J=7.0 Hz, 1, NH), 7.50 (s, 1,benzimidazole CH), 5.02 (d, J =4.9 Hz, 1, OH), 4.74 (t, J=5.1 Hz, 1, CH₂OH), 4.58 (d, J=5.1 Hz, 1, OH), 4.0-3.8 (m, 1, NCH), 3.8-3.7 (m, 2, 2OCH), 3.5-3.4 (m, 2, CH₂ O), 2.45-2.25 (m, 1, CH), 2.1-1.9 (m, 1, CH),1.4-1.2 (m, 1, CH); mass spectrum(CI): 337 (M+1); [α]²⁰ ₅₈₉ -106°, [α]²⁰₅₇₈ -118°, [α]²⁰ ₅₄₆ -182° (c=0.273, methanol).

Anal. Calcd. for C₁₂ H₁₄ N₂ Cl₂ O₅ : C, 42.75; H, 4.19; N, 8.31; Cl,21.03. Found: C, 42.84; H, 4.21; N, 8.24; Cl, 21.09.

Chromatography of the mother liquor contents on silica gel gave the (1R,2S)-isomer on elution with 7-8% methanol-chloroform; tworesolidifications from 90% ethanol gave (1R, 2S, 3R,5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediolas a yellow powder (1.57 g, 17%), m.p. 179°-181° C.; ¹ H-NMR(DMSO-d₆)δ:8.70 (d, J=7.1 Hz, 1, NH), 8.22 and 7.32 (both s, 1 each, 2benzimidazole CH), 5.28 (d, J=5.6 Hz, 1, OH), 4.77 (d, J=3.9 Hz, 1 OH),4.45 (t, J=4.9 Hz, 1, CH₂ OH), 4.1-3.9 (m, 3, 2 OCH and NCH), 3.6-3.5and 3.45-3.35 (both m partially overlapping H₂ O, 2, CH₂ O), 2.45-2.25(m, 1, CH), 2.1-3.9 (m, 1, CH), 1.35-1.25 (m, 1, CH); mass spectrum(CI):337(M+1); [α]²⁰ ₅₈₉ -15.6°, [α]²⁰ ₅₇₈ -13.2°, [α]²⁰ ₅₄₆ -4.00° (c=0.250,methanol).

Anal.. Calcd. for C₁₂ H₁₄ N₂ Cl₂ O₅ : C, 42.75; H, 4.19; N, 8.31; C,21.03. Found: C, 42.87; H, 4.15; N, 8.30; Cl, 21.14.

Elution with 8-10% methanol-chloroform gave white solid (2.9 g) which ¹H-NMR showed to be an approximately 1:1 mixture of the two isomers.

Continued elution of the column with 10-20% methanol-chloroform gavefractions containing additional (1S, 2R, 3R,5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediolwhich solidified from 90% ethanol to white powder (2.23 g) bringing thetotal yield of this isomer to 43%.

Example 55 (1S, 2R, 3R,5R)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate

(1S, 4R)-[4-(4,5-Dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol(3.75 g, 11.1 mmol) was acetylated in pyridine-acetic anhydride as inExample 38. The crude product was eluted from a silica gel column with2% methanol-chloroform and solidified from ethyl acetate to give (1S,2R, 3R,5R)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate as yellow powder (5.13 g, 100%), NMR identical to that ofExample 1. Such a sample was crystallized from ethyl acetate-hexanes togive title compound as yellow powder, m.p. 128°-130° C.; ¹H-NMR(DMSO-d₆) and mass spectrum (CI) identical to those of Example 1.;[α]²⁰ ₅₈₉ -95.8°, [α]²⁰ ₅₇₈ -107°, [α]²⁰ ₅₄₆ -165° (c=0.259, methanol).

Anal. Calcd. for C₁₈ H₂₀ N₂ Cl₂ O₈ : C, 46.67; H, 4.35; N, 6.05; Cl,15.31. Found: C, 46.74; H, 4.36; N, 5.96; Cl, 15.38.

Example 56 (1S, 2R, 3R,5R)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(1S, 2R, 3R,5R)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate (4.42 g, 9.97 mmol) was converted to title compound as withthe racemic sample described in Example 2. Crude product waschromatographed on silica gel with elution by 5% methanol-chloroform andsolvents evaporated to give (1S, 2R, 3R,5R)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate as an off-white solid foam from ethanol (4.0 g, 90%); ¹H-NMR(DMSO-d₆) and mass spectrum(CI) identical to those of racematedescribed in Example 2; [α]²⁰ ₅₈₉ +25.5°, [α]²⁰ ₅₇₈ +26.7°, [α]²⁰ ₅₄₆+30.6° (c=0.255, methanol).

Anal. Calcd. for C₁₉ H₂₀ N₂ Cl₂ O₆ : C, 51.49; H, 4.55; N, 6.32; Cl,16.00. Found: C, 51.33; H, 4.58; N, 16.27; Cl, 15.90.

Example 57 (1S, 2R, 3R,5R)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1S, 2R, 3R,5R)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (0.96 g, 2.17 mmol) and sodium carbonate (0.230 g, 2.17 mmol)were stirred in water (3 mL)-ethanol(15 mL)-methanol(15 mL) at ambienttemperature for 24 hours. The pH was adjusted to 7 with acetic acid andthe volatiles removed in vacuo. The residual solid was slurried in water(25 mL) and filtered. Resolidification from 2:1 ethanol-methanol gave(1S, 2R, 3R,5R)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolas white powder (408 mg, 60%), m.p. 222°-225° C.; ¹ H-NMR(DMSO-d₆)δ:8.49, 8.09, and 7.96 (all s, 1 each, 3 benzimidazole CH), 5.04 (d, J=7.0Hz, 1, OH), 4.87 (t, J=5.1 Hz, 1, CH₂ OH), 4.8-4.6 (m overlapping d at4.76, J=4.3 Hz, 2, NCH and OH), 4.25-4.10 (m, 1, OCH), 3.9-3.8 (m, 1,OCH), 3.6-3.45 (m, 2, CH₂ O), 2.45-2.25 (m, 1, CH), 2.2-2.0 (m, 1, CH),1.85-1.65 (m, 1, CH); mass spectrum(CI): 317 (M+1); [α]²⁰ ₅₈₉ -12.2°,[α]²⁰ ₅₇₈ -12.9°, [α]²⁰ ₅₄₆ -14.1° (c=0.255, methanol).

Anal. Calcd. for C₁₃ H₁₄ N₂ Cl₂ O₃ : C, 49.23; H, 4.45; N, 8.83; Cl,22.36. Found: C, 49.25; H, 4.47; N, 8.83; Cl, 22.46.

Example 58 (1S, 2R, 3R,5R)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1S, 2R, 3R,5R)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (2.00 g, 4.51 mmol) was dissolved in dry N,N-dimethylformamide(9 mL) and heated to 90° C. N-bromosuccinimide (1.62 g, 9.02 mmol) wasadded in four portions over 5 hours.. Volatiles were evaporated invacuo. The residue was chromatographed on silica gel and product waseluted with 30-50% ethyl acetate-hexanes as a yellow glass (1.00 g,43%); ¹ H-NMR(DMSO-d₆) consistent with structure. This sample wasdeblocked with sodium carbonate (203 mg, 1.9 mmol) in water (3mL)-ethanol(15 mL)-methanol(15 mL) at ambient temperature for 5 hours.The pH was adjusted to 7 with acetic acid. The solution was evaporatedto dryness in vacuo and the residue was triturated with water to givewhite powder which was chromatographed. Elution of a silica gel columnwith 10-12% methanol-chloroform gave (1S, 2R, 3R,5R)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolas white powder after solidification from 1:1 ethanol-methanol (410 mg,54%), m.p. 212°-215° C.; ¹ H-NMR(DMSO-d₆) and mass spectrum identicalwith those of racemate described in Example 4; [α]²⁰ ₅₈₉ -31.2°, [α]²⁰₅₇₈ -32.3°, [α]²⁰ ₅₄₆ -37.3° (c=0.260, methanol).

Anal. Calcd. for C₁₃ H₁₃ N₂ BrCl₂ O₃ : C, 39.43; H, 3.31; N, 7.07; totalhalogen as Cl, 26.86. Found: C, 39.62; H, 3.37; N, 7.02; total halogenas Cl, 26.75.

Example 59 (1S, 2R, 3R,5R)-5-(5,6-Dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

Title compound of Example 55 (514 mg, 1.11 mmol) was reduced with Raneynickel and hydrogen as in Example 56. Catalyst was filtered off, ethanolwas evaporated in vacuo, and glacial acetic acid (5 mL) substituted forformic acid. The acetic acid solution was refluxed for several hours.Acetic anhydride (5 mL) was added and reflux continued for 0.5 hour.Volatiles were evaporated in vacuo and the residual dark oil waschromatographed on silica gel. Elution with 4% methanol-chloroform gavefractions containing the triacetate of title compound as a yellow oil(0.46 g) with ¹ NMR consistent with structure. Deacetylation was carriedout with sodium carbonate as in Example 57. The solid obtained upontrituration with water was recrystallized from 1:1 methanol ethanol witha few drops of water to give (1S, 2R, 3R,5R)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolas white powder (220 mg, 75%), m.p. 222°-224° C.; .sup. 1H-NMR(DMSO-d₆)δ: 8.09 and 7.82 (both s, 1 each, 2 benzimidazole CH),5.09 (t, J=4.5 Hz, 1 CH₂ OH), 4.95 (d, J=7.2 Hz, 1, OH), 4.8-4.6 (moverlapping d at 4.75, J=3.9 Hz, 2, NCH and OH), 4.5-4.3 (m, 1, OCH),3.9-3.8 (m, 1, OCH), 3.7-3.45 (m, 2, CH₂ O), 2.59 (s overlappingsolvent, CH₃), 2.3-1.9 (m, 3, CH₂ and CH); mass spectrum(CI): 331(M+1);[α]²⁰ ₅₈₉ -58.6°, [α]²⁰ ₅₇₈ -62.0°, [α]²⁰ ₅₄₆ -70.8° (c=0.250,methanol).

Anal. Calcd. for C₁₄ H₁₆ N₂ Cl₂ O₃ : C, 50.78; H, 4.87; N, 8.46; Cl,21.41. Found: C, 50.85; H, 4.88; N, 8.45; Cl, 21.32.

Example 60 (1R, 2S, 3R,4R)-5,6-Dichloro-1-[2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl]-1H-benzimidazol-2 (3H)-one

Title compound of Example 55 (500 mg, 1.08 mmol) was reduced with Raneynickel and hydrogen as in Example 56. Catalyst was filtered off, ethanolevaporated in vacuo, and the residual oil dissolved in chloroform (50mL) and brought to reflux. 1,1'-Carbonyldiimidazole (845 mg, 4.40 mmol)was added in portions while the solution was refluxed for 3.5 hours. Thesolution was cooled and then extracted with water (2×20 mL), dried(sodium sulfate), and concentrated to a dark oil which waschromatographed on silica gel. Elution with 5% methanol-chloroform gavethe triacetate of title compound as a white powder (400 mg, 81%), ¹H-NMR consistent with structure. Deblocking was carried out in dioxane(10 mL) with sufficient 1N sodium hydroxide to bring the pH to 14. Afterone hour at ambient temperature, the pH was adjusted to 7 with 1Nhydrochloric acid. Volatiles were evaporated in vacuo and the residualsolid was chromatographed on silica gel. Product eluted with 10- 15%methanol-chloroform and was recrystallized from ethanol-water and thenfrom methanol-water to give (1R, 2S, 3R,4R)-5,6-dichloro-1-[2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl]-1H-benzimidazol-2(3H)-oneas white needles (130 mg, 45%), m.p. 219°-220° C.; ¹ H-NMR(DMSO-d₆)δ:11.2 (br m, 1, imidazole NH), 7.56 and 7.19 (both s, 1 each, 2benzimidazole CH), 4.9-4.7 (m, 2, 2OH), 4.7-4.45 (m, 2, OH and OCH),4.45-4.3 (m, 1, NCH), 3.80 (m, 1, OCH), 3.50 (m, 2, OCH₂), 2.1-1.8 (m,3, CH₂ and CH); mass spectrum(CI): 333(M+1); [α]²⁰ ₅₈₉ -3.60°, [α]²⁰ ₅₇₈-1.20°, [α]²⁰ ₃₆₅ +32.8° (c=0.253, methanol).

Anal. Calcd. for C₁₃ H₁₄ N₂ Cl₂ O₄ : C, 46.87; H, 4.24; N, 8.41; Cl,21.28. Found: C, 46.98; H, 4.26; N, 8.37; Cl, 21.30.

Example 61 (1R, 2S, 3R,5R)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclpentanediyldiacetate

(1R, 2S, 3R,5R)-5-(4,5-Dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol(1.30 g, 3.86 mmol) was stirred in pyridine (10 mL)-acetic anhydride(2.2 mL) at ambient temperature for 2 days. Volatiles were evaporated invacuo and the residue partitioned between chloroform and saturatedaqueous sodium bicarbonate. The chloroform layer was dried (sodiumsulfate) and concentrated to an oil which was chromatographed on silicagel. Elution with 2% methanol-chloroform gave (1R, 2S, 3R,5R)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate as yellow needles (1.60 g, 89%), after crystallization fromethyl acetate-hexanes, m.p. 125°-130° C.; ¹ H-NMR(DMSO-d₆) and massspectrum (CI) consistent with structure; [α]²⁰ ₅₈₉ -130.5°, [α]²⁰ ₅₇₈-140°, [α]²⁰ ₅₄₆ -178° (c=0.275, methanol).

Anal. Calcd. for C₁₈ H₂₀ N₂ Cl₂ O₈ : C, 46.67; H, 4.35; N, 6.05; Cl,15.31. Found: C, 46.76; H, 4.35; N, 6.08; Cl, 15.23.

Example 62 (1R, 2S, 3R,5R)-5-(5,6-Dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1R, 2S, 3R,5R)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate (1.29 g, 2.78 mmol) in n-propanol (100 mL) was shaken withRaney nickel (Aldrich, slurry in water, 200 mg wet) under hydrogen (40psi) on a Parr shaker for 4 hours. Catalyst was filtered off with Celiteand the volatiles were evaporated in vacuo. The residual oil wasrefluxed in 96% formic acid (45 mL) for 5 hours. Concentratedhydrochloric acid (5 mL) was added and reflux continued for anadditional 4 hours. Volatiles were evaporated in vacuo and the residuewas dissolved in 1N sodium hydroxide (10 mL). The solution was stirredat ambient temperature for 18 hours, neutralized with acetic acid, andconcentrated in vacuo. The residue was chromatographed on silica gel.Elution with 15% methanol-chloroform gave (1R, 2S, 3R,5R)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediolas white powder (236 mg, 26%), m.p. 198°-200° C.; ¹ H-NMR(DMSO-d₆)δ:8.30 and 7.72 (both s, 1 each, 2 aromatic CH), 5.0-4.8 (m, 3, 2 OH andNCH), 4.56 (t, J=5.1 Hz, 1, CH₂ OH), 4.2-4.1 (m, 2, 2 OCH), 3.8-3.5 (m,2, CH₂ O), 2.58 (s, 3, CH₃), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 2, CH₂);mass spectrum(CI): 331(M+1); [α]²⁰ ₅₈₉ -13.5°, [α]²⁰ ₅₇₈ -13.9°, [α]²⁰₅₄₆ -15.9°, [α]²⁰ ₄₃₆ -30.3° (c=0.251, methanol).

Anal. Calcd. for C₁₄ H₁₆ N₂ Cl₂ O₃ : C, 50.78; H, 4.87; N, 8.46; Cl,21.41. Found: C, 50.68; H, 4.88; N, 8.39; Cl, 21.31.

Example 63 (1R, 4S)-4-Amino-2-cyclopentene-1-methanol

A mixture of (-)-(1S, 4R)-4-amino-2-cyclopentene-1-carboxylic acid(Chiros Ltd., Cambridge, England; 40.00 g, 0.315 mole) in drytetrahydrofuran (300 mL) was stirred in an ice bath while 1M lithiumaluminum hydride in tetrahydrofuran (Aldrich, 485 mL) was added over 1.5hours. The temperature during this addition was not allowed to exceed 0°C. The mixture was brought to ambient temperature and then to refluxover one hour and maintained at reflux for 2.5 hours. The mixture wasallowed to cool to ambient temperature and sodium fluoride (89.6 g) wasadded and stirring continued for an additional 0.5 hour. The mixture wascooled (ice bath) and water (23 mL) added slowly. Stirring was continuedfor an additional 0.5 hour. The precipitate was filtered and extractedwith 40% methanol-tetrahydrofuran (2×300 mL). The filtrate-wash wasconcentrated in vacuo to a colorless oil which darkened rapidly in airand light and was used immediately (Example 64). Such a sample was driedat ambient temperature/0.2 mm Hg to a pale yellow oil; ¹ H-NMR(DMSO-d₆)identical to that of the enantiomer described in Example 22, δ: 5.67 (m,2, CH═CH), 3.8-3.7 (m, 1, CHN), 3.32 (d, J=6.0 Hz, overlapped by broadD₂ O-exchangeable peak centered at 3.18, CH₂ O, OH, NH₂ and H₂ O insolvent), 2.68-2.56 (m, 1, H-1), 2.28-2.18 (m, 1, 1/2CH₂), 1.08-0.98 (m,1, 1/2CH₂); mass spectrum(CI): 114(M+1); [α]²⁰ ₅₈₉ +55.0°, [α]²⁰ ₅₇₈+58.3°, [α]²⁰ ₅₄₆ +67.4°, [α]²⁰ ₄₃₆ +119° (c=0.242, methanol).

Anal. Calcd. for C₆ H₁₁ NO.0.31 H₂ O: C, 60.69; H, 9.86; N, 11.80.Found: 61.12; H, 9.79; N, 11.38.

Example 64 (1R,4S)-[4-(4,5-Dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol

The filtrate-wash from Example 63 was concentrated and t-butanol (400mL) was added to the residual oil. This solution was used for thecondensation with 1,2,4-trichloro-5-nitrobenzene (Aldrich, 71.3 g, 0.315mole as 97%) by the method of Example 33. The reaction mixture, afterevaporation of volatiles in vacuo, was chromatographed on a silica gelcolumn eluted with 1:1 hexanes-ethyl acetate and ethyl acetate.Rechromatography of the crude product on silica gel was carried out withelution of by 4-6% methanol-chloroform. Combined product-containingfractions yielded 58 grams of reddish solid on evaporation of solvents.This solid was resolidified from ethyl acetate-hexanes to give (1R,4S)-[4-(4,5-dichloro-2 -nitroanilino)-2-cyclopenten-1-yl]methanol asyellow powder (34.5 g, 36% from (-)-(1S,4R)-4-amino-2-cyclopentene-1-carboxylic acid); m.p. 95°-97° C.; ¹H-NMR(DMSO-d₆) and mass spectrum(CI) identical with those of theenantiomer described in Example 53; [α]²⁰ ₅₈₉ -195°, [α]²⁰ ₅₇₈ -217°,[α]²⁰ ₅₄₆ -326° (c=0.350, methanol).

Anal. Calcd. for C₁₂ H₁₂ N₂ Cl₂ O₃ : C, 47.55; H, 3.99; N, 9.24; Cl,23.39. Found: C, 47.56; H, 4.01; N, 9.25; Cl, 23.30.

Continued elution of the column (above) gave additional yellow powder(18.0 g, 19%) which ¹ -NMR showed to be additional title compoundcontaminated by ca. 15% of (1R,4S)-[4-(2,5-dichloro-4-nitroanilino)-2-cyclopenten-1-yl]methanol.

Example 65 (1R, 2S, 3S,5S)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate and (1S, 2R, 3S,5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate

(1R, 4S)-[4-(4,5-Dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol(17.00 g, 56.1 mmol) was hydroxylated and the mixture of triols wasacetylated as in Example 38. The crude red oil isolated afteracetylation was chromatographed on silica gel and a mixture of titlecompounds eluted with 2% methanol-chloroform. Fractional crystallizationfrom ethyl acetate-hexanes gave (1R, 2S, 3S,5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate as yellow needles in two crops (12.78 g, 49%), m.p. 127°-128°C.; ¹ H-NMR(DMSO-d₆) and mass spectrum (CI) identical to those of theracemic sample described in Example 1 and the enantiomer described inExample 55; [α]²⁰ ₅₈₉ +106°, [α]²⁰ ₅₇₈ +119°, [α]²⁰ ₅₄₆ +184° (c=0.275,methanol).

Anal. Calcd. for C₁₈ H₂₀ N₂ Cl₂ O₈ : C, 46.67; H, 4.35; N, 6.05; Cl,15.31. Found: C, 46.74; H, 4.40; N, 6.09; Cl, 15.22.

Continued fractional crystallization of the mother liquor contents fromethyl acetate-hexanes gave (1S, 2R, 3S,5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate as orange crystals (2.45 g, 10%), m.p. 122°-124° C.; ¹H-NMR(DMSO-d₆) identical with that of the chiral sample described inExample 61.

Evaporation of combined mother liquors gave an additional 9.50 g (40%)of an approximately 1:1 (by ¹ H-NMR) mixture of the title compounds.

Example 66 (1R, 2S, 3S,5S)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(1R, 2S, 3S,5S)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate was converted to title compound as in Example 2. The crudeproduct after formic acid treatment was chromatographed on silica gelwith elution by 10% ethyl acetate-hexanes. Evaporation ofproduct-containing fractions left (1R, 2S, 3S,5S)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate as a white solid foam from ethyl acetate (1.85 g, 95%); ¹H-NMR(DMSO-d₆) and mass spectrum(CI) identical to those of racematedescribed in Example 2 and enantiomer described in Example 56; [α]²⁰ ₅₈₉-25.5°, [α]²⁰ ₅₇₈ -27.0°, [α]²⁰ ₅₄₆ -31.2° (c=0.333, methanol).

Anal. Calcd. for C₁₉ H₂₀ N₂ Cl₂ O₆.0.1 EtOAc: C, 51.54; H, 4.64; N,6.20; Cl, 15.68. Found: C, 51.29; H, 4.69; N, 6.19; Cl, 15.91.

Example 67 (1S, 2R, 3S,5S)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanedioland (1R, 2S, 3S,5S)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

An ca. 1:1 mixture of (1R, 2S, 3S,5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate and (1S, 2R, 3S,5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyldiacetate (4.30 g, 9.28 mmol) was deacetylated with sodium carbonate (97mg) in 1:1:1 water-ethanol-methanol (100 mL) at ambient temperature for24 hours. The pH was adjusted to 7 with acetic acid and the volatilesremoved in vacuo. The residual solid was extracted with methanol. Themethanol filtrate was evaporated to dryness in vacuo. The residual solidwas dissolved in ethanol (55 mL)-water (20 mL), adjusted to pH 5-6 withsulfuric acid, and refluxed with iron powder (325 mesh, 99.9%, Aldrich,5.18 g, 93 mequiv) and iron(II) sulfate heptahydrate (Aldrich, 98+%,1.30 g, 4.58 mequiv) for 4 hours. Solids were filtered off and theethanol filtrate-wash concentrated to an oil. Triethylorthoformate (55mL) and methanesulfonic acid (0.05 mL) were added to the oil and theresulting solution stirred at ambient temperature for 18 hours.Concentration in vacuo left an oil which was redissolved in 1Nhydrochloric acid (50 mL)-dioxane(5 mL). After 2.5 hours, the pH wasadjusted to 7 with 1N sodium hydroxide and the volatiles evaporated invacuo. The residual solids were chromatographed on silica gel. Elutionwith 10-12% methanol-chloroform gave fractions containing (1S, 2R, 3S,5S)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol,which was isolated as white crystals (540 mg, 18%) after crystallizationfrom ethyl acetate-hexanes, m.p. 201°-202° C.; ¹ H-NMR(DMSO-d₆)δ: 8.42,8.07, and 7.92 (all s, 1 each, 3 benzimidazole CH), 5.1-4.8 (moverlapping d at 5.02, J=5.7 Hz, and d at 4.93, J=3.9 Hz, total 3, NCHand 2 OH), 4.54 (t, J= 4.8 Hz, 1, OH), 4.2-4.0 (m, 2, 2 OCH), 3.75-3.45(m, 2, OCH₂), 2.4-1.9 (m, 3, CH₂ and CH); mass spectrum(CI): 317 (M +1);[α]²⁰ ₅₈₉ -61.4°, [α]²⁰ ₅₇₈ -63.1°, [α]²⁰ ₅₄₆ -72.9° (c=0.350,methanol).

Anal. Calcd. for C₁₃ H₁₄ N₂ Cl₂ O₃ : C, 49.23; H, 4.45; N, 8.83; Cl,22.36. Found: C, 49.20; H, 4.45; N, 8.78; Cl, 22.37.

Continued elution of the column with 15-20% methanol-chloroform gavefractions containing a mixture of the title compounds followed byfractions containing only (1R, 2S, 3S,5S)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol,which was isolated as white crystals (605 mg, 21%) on crystallizationfrom 10% methanol-ethyl acetate, m.p. 221°-222° C.; ¹ H-NMR(DMSO-d₆) andmass spectrum(CI) identical with those of the enantiomer described inExample 57; [α]²⁰ ₅₈₉ +14.5°, [α]²⁰ ₅₇₈ +15.2°, [α]²⁰ ₅₄₆ +16.9°(c=0.290, methanol).

Anal. Calcd. for C₁₃ H₁₄ N₂ Cl₂ O₃ : C, 49.23; H, 4.45; N, 8.83; Cl,22.36. Found: C, 49.29; H, 4.46; N, 8.87; Cl, 22.26.

Example 68 (1R, 2S, 3S,5S)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(1R, 2S, 3S,5S)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (1.40 g, 2.94 mmol) was brominated as in Example 3. Volatileswere removed in vacuo and the residue chromatographed on silica gel.Crude product eluted with 20-30% hexane-ethyl acetate as a colorlessoil. A chloroform solution of the oil was washed with water in order toremove contaminating succinimide. The chloroform solution was dried(sodium sulfate) and evaporated to dryness in vacuo to give titlecompound as white solid foam from ethanol (760 mg, 50%); ¹ H-NMR(DMSO-d₆) and mass spectrum(CI) identical to racemate described inExample 3; [α]²⁰ ₅₈₉ +43.8°, [α]²⁰ ₅₇₈ +45.2°, [α]²⁰ ₅₄₆ 52.2° (c=0.345,methanol).

Anal. Calcd. for C₁₉ H₁₉ N₂ BrCl₂ O₆.0.05 EtOH: C, 43.74; H, 3.71; N,5.34; total halogen as Cl, 20.28. Found: C, 43.74; H, 3.69; N, 5.35;total halogen as Cl, 20.41.

Example 69 (1R, 2S, 3S,5S)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1R, 2S, 3S,5S)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (660 mg, 1.26 mmol) was deacetylated as in Example 4 to givetitle compound as white powder after solidification from 1:1ethanol-methanol (415 mg, 83%), m.p. 213°-216° C.; ¹ H-NMR(DMSO-d₆) andmass spectrum(CI) identical with those of racemate described in Example4; [α]²⁰ ₅₈₉ +35.9°, [α]²⁰ ₅₇₈ +36.8°, [α]²⁰ ₅₄₆ +42.1° (c=0.340,methanol).

Anal. Calcd. for C₁₃ H₁₃ N₂ BrCl₂ O₃ : C, 39.43; H, 3.31; N, 7.07; totalhalogen as Cl, 26.86. Found: C, 39.48; H, 3.29; N, 7.00; total halogenas Cl, 26.90.

Example 70 (±)-4,5-Dichloro-N-(2-cyclopenten-1-yl)-2-nitroaniline

3-Aminocyclopentene hydrochloride (R. Vince and S. Daluge, J. Med. Chem.1974, 17,578) (5.10 g, 42.8 mmol), 1,2,4-trichloro-5-nitrobenzene(Aldrich, 10.0 g, 42.8 mmol), and potassium carbonate (98%, Aldrich,15.00 g, 107 mmol) were refluxed in t-butyl alcohol (100 mL) undernitrogen for 24 hours. Volatiles were evaporated in vacuo and theresidue chromatographed on silica gel. Title compound was eluted with20-30% chloroform-hexanes as an orange powder (5.14 g, 44%), m.p.85°-86° C.; ¹ H-NMR(DMSO-d₆)δ: 8.27 (s, 1, aromatic CH), 7.88 (d, J=7.3Hz, 1, NH), 7.48 (s, 1, aromatic CH), 6.2-6.0 (m, 1, ═CH), 6.0-5.8 (m,1, ═CH), 5.0-4.7 (m, 1, NCH), 2.6-2.2 (m overlapping solvent, 3 CH),1.8-1.5 (m, 1, 1/2CH₂); mass spectrum(CI): 273 (M +1).

Anal. Calcd. for C₁₁ H₁₀ N₂ Cl₂ O₂ : C, 48.37; H, 3.69; N, 10.26; Cl,25.96. Found: 48.39; H, 3.72; N, 10.28; Cl, 25.87.

Example 71 (±)-(1R*, 2S*,3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclopentanediol and (±)-(1S*,2R*, 3R*)-3-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediol

(±)-4,5-Dichloro-N-(2-cyclopenten-1-yl)-2-nitroaniline (6.30 g, 23.1mmol) was hydroxylated as in Example 38. Volatiles were evaporated invacuo and the residue was chromatographed on silica gel. A mixture oftitle compounds was eluted with 10% methanol-chloroform as a orangesolid (7.00 g). Crystallization from ethanol-water gave (±)-(1S*, 2R*,3R*)-3-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediol as orangepowder (4.03 g, 57%), m.p. 134°-136° C.; ¹ H-NMR(DMSO-d₆)δ: 8.72 (d,J=7.6 Hz, 1, NH), 8.25 and 7.36 (both s, 1 each, 2 aromatic CH), 5.25(d, J=4.5 Hz, 1, OH), 4.80 (d, J=5.1 Hz, 1, OH), 4.14-3.86 (m, 3, 2 OCHand 1 NCH), 2.2-2.1 (m, 1, CH), 1.8-1.4 (m, 3, CH and CH₂); massspectrum(CI): 307(M+1).

Anal. Calcd. for C₁₁ H₁₂ N₂ Cl₂ O₄ : C, 43.02; H, 3.94; N, 9.12; Cl,23.09. Found: C, 43.09; H, 3.99; N, 9.03; Cl, 23.03.

Concentration of the mother liquor gave additional orange solid (2.86 g)which ¹ H-NMR showed to be an approximately 1:1 mixture of(+/-)-(±)-(1R*, 2S*,3R*)-3-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediol (NMR spectrumdescribed in Example 16) and (±)-(1S*, 2R*,3R*)-3-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediol.

Example 72 (±)-(1S*, 2R*,3R*)-3-(5,6-Dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediol

(±)-(1S*, 2R*, 3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclopentanediol(3.77 g, 12.3 mmol) in isopropanol (250 mL) was shaken in a Parr shakerwith Raney nickel (Aldrich, prewashed with water until neutral, ca. 1tsp) under hydrogen (50 psi) for 2 hours, at which point uptake ofhydrogen had ceased. TLC (silica gel, methanol:chloroform/1:10) showsone spot at lower R_(f) than starting material. The catalyst wasfiltered off (Celite) and volatiles evaporated to leave a glass whichwas refluxed in formic acid (65 mL) for 40 minutes. The formic acid wasevaporated and the residual oil dissolved in ethanol (50 mL) andadjusted to pH 13 with 5N sodium hydroxide. After stirring at ambienttemperature for 18 hours, the pH was adjusted to 7 with hydrochloricacid and the volatiles removed by evaporation in vacuo. The residue wastriturated with methanol. The methanol solution was evaporated todryness to give white solid which contained product and some salts (7.41g). A portion of this solid (1.05 g) was chromatographed on silica geland product was eluted with 6-8% methanol-chloroform as white powder,after solidification from ethanol (350 mg), m.p. 180°-182° C.; ¹H-NMR(DMSO-d₆)δ: 8.46, 8.08, and 7.93 (all s, 1 each, 3 aromatic CH),4.96 (d, J=4.7 Hz, 1, OH), 4.92-4.85 (m, 1, NCH), 4.81 (d, J=5.9 Hz, 1,OH), 4.19-4.11 (m, 1, OCH), 4.08-3.93 (m, 1, OCH), 2.38-2.04 (m, 2,CH₂), 2.03-1.72 (m, 2, CH₂); mass spectrum(CI): 287 (M+1).

Anal. Anal. Calcd. for C₁₂ H₁₂ N₂ Cl₂ O₂ : C, 50.19; H, 4.21; N, 9.76;Cl, 24.69. Found: C, 50.18; H, 4.24; N, 9.74; Cl, 24.60.

Example 73 (±)-(1S*, 2R*,3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate

(±)-(1S*, 2R*,3R*)-3-(5,6-Dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediol (3.00 g,10.5 mmol) was acetylated and brominated as in Example 39 and the titlecompound eluted from a silica gel column with 1% methanol-chloroform togive product as tan solid foam (2.86 g, 66%). Further purification ofsuch a sample by chromatography on silica gel with elution by 10%hexanes-chloroform followed by resolidification from methanol gave(±)-(1S*, 2R*, 3R*)-3-(2-bromo-5,6-dichloro-1H-cyclopentanediyldiacetate as yellow powder, m.p. 203°-205° C.; ¹ H-NMR (DMSO-d₆)δ: 8.03and 7.93 (both s, 1 each 2 aromatic CH), 5.42-5.33 (m, 3, 2 OCH andNCH), 2.69-2.62 (m, 1, 1/2CH₂), 2.28-2.09 (m, 6, CH₂, CH, and CH₃),1.54-1.51 (m, 3, CH₃); mass spectrum (CI): 455 (7.1), 453 (47), 451(100), 449 (455, M+1).

Anal. Calcd. for C₁₆ H₁₅ N₂ Cl₂ BrO₄ : C, 42.69; H, 3.36; N, 6.22; totalhalogen as Cl, 23.63. Found: C, 42.77; H, 3.39; N, 6.17; total halogenas Cl, 23.62.

Example 74 (1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(1R, 2S, 3S,5S)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (500 mg. 0.958 mmole) was refluxed in water:ethanol/2:1 (7.5mL) with cyclopropylamine (freshly opened ampoule from Aldrich, 0.66 mL,9.6 mmole) under nitrogen for 18 hours. TLC (silica gel, 10%methanol-chloroform) showed complete conversion to a single spot withlower R_(f) than starting material. 1N sodium hydroxide (0.96 mL) wasadded and volatiles were evaporated. The residue was chromatographed ona silica gel flash column. Title compound was eluted with 10%methanol-chloroform as a colorless glass which solidified fromwater:ethanol/2:1 (5 mL) to give white powder (170 mg, 48%), m.p.219°-220° C.; ¹ H-NMR(DMSO-d₆)δ: 7.64 and 7.46 (both s, 2, aromatic CH),7.11 (m, 1, NH), 5.11 (t, J=4.3 Hz, 1, OH), 4.77 (d, J=7.0 Hz, 1, OH),4.67 (d, J=3.7 Hz, 1, OH), 4.65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m,1, OCH), 3.7-3.4 (m, 2, OCH₂), 2.85-2.70 (m, 1, NCH of cyclopropyl),2.15-1.80 (m, 3, CH₂ and CH of cyclopentane), 0.80-0.50 (m, 4, 2 CH₂ ofcyclopropyl); mass spectrum (CI): 372(M+1); [α]²⁰ ₅₈₉ +13.4°, [α]²⁰ ₅₇₈+15.5°, [α]²⁰ ₅₄₆ +16.9° (c=0.277, methanol).

Anal. Calcd. for C₁₆ H₁₉ N₃ Cl₂ O₃ : C, 51.63; H, 5.15: N, 11.29; Cl,19.05. Found: C, 51.36; H, 5.06; N, 11.25; Cl, 19.16

Example 75 (1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(1R, 2S, 3S,5S)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (1.00 g, 1.92 mmole) was refluxed in ethanol (10 mL) withisopropylamine (1.6 mL, Fluka) under nitrogen for 24 hours. A secondportion of isopropylamine (0.80 mL) was added and reflux continued foran additional 4 hours. Volatiles were evaporated, the residue wasredissolved in ethanol, 1N sodium hydroxide (1.90 mL) was added, andvolatiles were reevaporated. The residue was chromatographed on a silicagel column. Title compound was eluted with 10% methanol-ethyl acetate asa colorless glass. Concentration of an ethanol solution gave titlecompound as a off-white solid foam (360 mg, 46%). Such a sample wassolidified by trituration with 95% water-5% methanol to give titlecompound as white powder (96%), m.p. 137°-138° C.; ¹ H-NMR(DMSO-d₆)δ:7.60 and 7.39 (both s, 2, aromatic CH), 6.64 (d, J=7.4 Hz, 1, NH), 5.14(t, J=4.3 Hz, 1, OH), 4.81 (d, J=7.3 Hz, 1, OH), 4.70 (d, J=3.5 Hz, 1,OH), 4.70-4.50 (m, 1, NCH), 4.50-4.30 (m, 1, OCH), 4.10-4.00 (m, 1, NCHof cyclopropylamino), 3.9-3.75 (m, 1, OCH), 3.70-3.50 (m, 2, OCH₂),2.20-1.80 (m, 3, CH₂ and CH of cyclopentane), 1.24 (d, J=6.6 Hz, 6, 2CH₃); mass spectrum (CI): 374(M+1); [α]²⁰ ₅₈₉ -3.72°, [α]²⁰ ₅₇₈ -2.60°,[α]²⁰ ₅₄₆ -2.23°, [α]²⁰ ₄₃₆ -9.67°, [α]²⁰ ₃₆₅ -51.7° (c=0.269,methanol).

Anal. Calcd. for C₁₆ H₂₁ N₃ Cl₂ O₃.1.3 H₂ O: C, 48.32; H, 5.98; N,10.57; Cl, 17.83. Found: C, 48.08; H, 5.91; N, 10.41; Cl, 18.13.

Example 76 (±)-(1R*, 2S*, 3S*,5S*)-5-(5,6-Dichloro-2-amino-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (750 mg, 1.44 mmol) was dissolved in ethanol (10 mL).Hydrazine hydrate (55%, 0.41 mL, 7.2 mmol) was added and the solutionwas refluxed for 2 hours. Volatiles were evaporated and the residualwhite solid was resolidified from ethanol-water and stirred with Raneynickel (preequilibrated under hydrogen) in methoxyethanol (20 mL) for 30minutes. Catalyst was filtered off and the filtrate made slightly basicwith aqueous sodium hydroxide to complete removal of the acetate groups.The solution was neutralized, and volatiles evaporated. The residualsolid was recrystallized from ethanol-water to give title compound aspale pink solid (97 mg, 20%), m.p. 283°-284° C. dec.; ¹ H-NMR(DMSO-d₆)δ:7.61 and 7.30 (both s, 2, aromatic CH), 6.65 (br s, 2, NH₂), 5.07 (t,J=4.3 Hz, 1, OH), 4.80 (d, J=7.0 Hz, 1, OH), 4.66 (d, J=3.7 Hz, 1, OH),4.65-4.50 (m, 1, NCH), 4.45-4.30 (m, 1, OCH), 3.90-4.80 (m, 1, OCH),3.70-3.40 (two m, 2, OCH₂), 2.20-1.80 (m, 3, CH₂ and CH ofcyclopentane); mass spectrum (CI): 332 (M+1).

Anal. Calcd. for C₁₃ H₁₅ N₃ Cl₂ O₃ : C, 47.01; H, 4.55; N, 12.65; Cl,21.35. Found: C, 46.72; H, 4.60; N, 12.46; Cl, 21.08.

Example 77 (±)-(1R*, 2R*,4S*)-2-(2-Cyclopropylamino-5,6-dichloro-1H-benzimidazol-1-yl)-4-(hydroxymethyl)cyclopentanol

(±)-(1R*, 2R*,4S*)-4-(Acetoxymethyl)-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-cyclopentylacetate (500 mg, 1.50 mmol) was reacted with cyclopropylamine (0.73 mL)in the manner of Example 74. Crude product was chromatographed on silicagel and title compound eluted with 5% methanol-ethyl acetate as acolorless glass which solidified from ethyl acetate-hexanes to whitepowder (180 mg, 48%), m.p. 251°-253° C.; ¹ H-NMR(DMSO-d₆)δ: 7.54 and7.45 (both s, 2, aromatic CH), 5.04 (d, J=5.1 Hz, 1, OH), 4.97 (t, J=4.7Hz, 1, OH), 4.60-4.50 and 4.50-4.30 (both m, 1 each, NCH and OCH), 3.50(m, 2, OCH₂), 2.80 (m, 1, CH), 2.35-2.10 (m, 1, CH), 2.05-1.80 (m, 3,CH₂ and CH of cyclopentane), 1.80-1.60 (m, 1, CH), 0.80-0.50 (1 m, 4,2CH₂ of cyclopropyl); mass spectrum (CI): 356 (M+1).

Anal. Calcd. for C₁₆ H₁₉ N₃ Cl₂ O₂ : C, 53.97; H, 5.34; N, 11.80; Cl,19.91. Found: C, 53.72; H, 5.42; N, 11.52; Cl, 19.64.

Example 78 (±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(cyclobutylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (7 mL)and cyclobutylamine (0.41 mL, 4.8 mmol) was added. The solution wasrefluxed under nitrogen for 18 hours. Volatiles were evaporated and theresidue stirred in methanol half-saturated with ammonia at 0° C. (20 mL)for 18 hours. Volatiles were removed in vacuo and the residuecrystallized from ethanol-water to give title compound as white solid,m.p. 250° C. dec.; ¹ H-NMR(DMSO-d₆)δ: 7.61 and 7.38 (both s, 1 each,aromatic CH), 7.07 (d, J=7.4 Hz, 1, NH), 5.15 (t, J=3.9 Hz, 1, OH), 4.81(d, J=7.3 Hz, 1, OH), 4.71-4.45 (m overlapping d at 4.71, J=3.5 Hz,total 2, OH and NCH), 4.40-4.30 (m, 2. OCH and NCH), 3.82-3.80 (m, 1,OCH), 3.72-3.42 (both m, 1 each, OCH₂), 2.32-1.67 (three m, 9, 4CH₂ andCH); mass spectrum (CI): 386(M +1).

Anal. Calcd. for C₁₇ H₂₁ N₃ Cl₂ O₃.0.15 H₂ O.0.05 C₂ H₅ OH: C, 52.49; H,5.56; N, 10.74; Cl, 18.12. Found: C, 52.34; H, 5.47; N, 10.52; Cl,17.99.

Example 79 (±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (500 mg, 0.958 mmol) was dissolved in ethanol (7 mL).Azetidine (Aldrich, 250 mg, 4.4 mmol as 98%) was added and the solutionwas refluxed under nitrogen for 48 hours. Methanolic ammonia (saturatedat 0° C., 20 mL) was added to the cooled solution and this solution wasstirred for an additional 18 hours. Volatiles were evaporated, theresidue was redissolved in ethanol (10 mL) and 1N sodium hydroxide (0.96mL) was added. Volatiles were evaporated and the residual solids weretriturated with water (3 mL) and filtered. Resolidification of the solidfrom acetonitrile-methanol gave title compound as white powder (146 mg,41%), m.p. 221°-222° C.; ¹ H-NMR(DMSO-d₆)δ: 7.78 and 7.53 (both s, 1each, 2 aromatic CH), 5.05 (t, J=4.3 Hz, 1, OH), 4.91 (d, J=5.3 Hz, 1,OH), 4.59 (d, J=3.7 Hz, 1, OH), 4.45-4.40 (m, 2, OCH and NCH), 4.25-4.15(m, 4, 2 CH₂ N), 3.82-3.79 (m, 1, OCH), 3.66-3.43 (both m, 1 each,OCH₂), 2.40-2.32 (m, 2, CH₂), 2.03-1.95 (m, 3, CH₂ and NCH); massspectrum (CI): 372(M+1).

Anal. Calcd. for C₁₆ H₁₉ N₃ Cl₂ O₃ : C, 51.63; H, 5.14; N, 11.29; Cl,19.05. Found: C, 51.45; H, 5.10; N, 11.27; Cl, 18.96.

Example 80 (±)-(1R*, 2S*, 3R*,5R*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)(1R*, 2S*, 3R*,5R*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (Example 39, 1.00 g, 1.87 mmol), cyclopropylamine (Aldrich,1.7 mL, 24 mmol) and absolute ethanol (10 mL) were refluxed undernitrogen for 48 hours. The reaction was cooled and 1N sodium hydroxide(1.2 mL) was added. Volatiles were evaporated in vacuo and the residualoily solid was chromatographed on silica gel. Elution with 5%methanol-ethyl acetate gave fractions containing white powder (200 mg).Recrystallization from 1:1 water-ethanol gave (+/-)-(1R*, 2S*, 3R*,5R*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediolas white crystals (180 mg, 40%); m.p. >250° C.; ¹ H-NMR(DMSO-d₆)δ: 7.70(m, 1, NH), 7.62 and 7.39 (both s, 1 each, 2 benzimidazole CH), 5.77 (brs, 1, OH), 5.13 (d, J=5.3 Hz, 1, OH), 4.95-4.80 (m, 1, CHN), 4.48 (t,J=4.7 Hz, 1, CH₂ OH), 4.2-4.0 (m, 2, 2 OCH), 3.7-4.0 (m, 2, OCH₂),2.9-2.65 (m, 1, OCH), 2.2-1.8 (m, 3, CH₂ and CH); mass spectrum (CI):372(M+1).

Anal. Calcd. for C₁₆ H₁₉ N₃ Cl₂ O₃ : C, 51.63; H, 5.14; N, 11.29; Cl,19.05. Found: C, 51.53; H, 5.18; N, 11.22; Cl, 18.97.

Example 81 (±)-(1R*, 2S*, 3R*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-methyl-1,2-cyclopentanediol

Part A. (±)-(1S*, 2R*, 3R*,5R*)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (Example 2, 3.00 g, 6.77 mmol) was dissolved in methanol (100mL). Methanol saturated with ammonia at 0° C. (100 mL) was added and thesolution stirred at ambient temperature overnight. Volatiles wereevaporated in vacuo and the residual solid slurried with water andfiltered to give title compound as tan powder (2.02 g, 94%); ¹H-NMR(DMSO-d₆) identical with that of single enantiomer (Example 57).

Part B. (±)-(1R*, 2S*, 3R*,5S*)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-iodo-1,2-cyclopentanediol

(±)-(1S*, 2R*, 3R*,5R*)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol(Part A, 2.00 g, 6.31 mmol) was dissolved in dry DMF (15 mL) undernitrogen and cooled (ice bath) while a solution ofmethyltriphenoxyphosphonium iodide (Aldrich, 3.27 g, 6.94 mmol) in dryDMF (15 mL) was added dropwise over 20 minutes. Stirring was continuedin the ice bath for an additional 30 minutes and then at ambienttemperature for 18 hours. Volatiles were evaporated in vacuo and theresidue chromatographed on silica gel. Product was eluted with 2%methanol-chloroform to give, after evaporation of solvents, a paleyellow powder (750 mg, 28%); ¹ H-NMR(DMSO-d₆)δ: 8.51, 8.08, and 7.97(all s, 1 each, 3 benzimidazole CH), 5.20 (d, J=6.7 Hz, 1, OH), 5.04 (d,J=4.9 Hz, 1, OH), 4.8-4.6 (m, 1, NCH), 4.3-4.2 (m, 1, OCH), 3.8-3.7 (m,1, OCH), 3.6-3.4 (m, 2, CH₂ I), 2.55-2.40 (m, CH overlapping solvent),2.35-2.20 (m, 1, CH), 1.75-1.50 (m, 1, CH).

Part C. (±)-(1R*, 2S*, 3R*,5S*)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-methyl-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3R*,5S*)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-iodo-1,2-cyclopentanediol(Part B, 0.73 g, 1.71 mmol) in ethanol (200 mL) was shaken with 5% Pd oncarbon (140 mg) with triethylamine (0.24 mL) under hydrogen (50 psi) ona Parr shaker for 7.5 hours. The catalyst was filtered off (Celite) andthe ethanol filtrate evaporated to a white solid. To this solid wasadded pyridine (15 mL) and acetic anhydride (1.3 mL). The resultingsolution was stirred at ambient temperature for 18 hours. The volatileswere evaporated and the residual oil was dissolved in chloroform (50mL). The chloroform solution was extracted with aqueous sodiumbicarbonate and dried (sodium sulfate). Evaporation of the chloroformleft title compound as a yellow glass (560 mg, 85%); ¹ H-NMR(DMSO-d₆)δ:8.61, 8.15, and 7.97 (all s, 1 each, 3 benzimidazole CH), 5.60-5.45 (m,1, OCH), 5.20-4.95 (m, 2, OCH and NCH), 2.50-2.15 (m, 3, CH₂ and CH),2.09 and 1.95 (both s, 3 each, 2 OAc), 1.20 (d, J=6.5 Hz, 3, CHCH₃).

Part D. (±)-(1R*, 2S*, 3R*,5S*)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-methyl-1,2-cyclopentanediyldiacetate

(±)-(1R*, 2S*, 3R*,5S*)-5-(5,6-Dichloro-1H-benzimidazol-1-yl)-3-methyl-1,2-cyclopentanediyldiacetate (Part C, 550 mg, 1.43 mmol) was dissolved in drytetrahydrofuran (15 mL). N-bromosuccinimide (520 mg, 2.92 mmol) wasadded and the resulting solution refluxed vigorously for 10 minutes. Anadditional portion of N-bromosuccinimide (100 mg) was added and refluxcontinued an additional 5 minutes. At this point, TLC (silical gelplates developed with 5% methanol-chloroform) showed starting materialhas been converted to a slightly higher R_(f) UV-absorbing spot. Thereaction mixture was quenched by cooling (ice bath) and diluted withchloroform (50 mL). This solution was washed with water and dried(sodium sulfate). Evaporation left a yellow solid which waschromatographed on silica gel. Title compound was eluted with 5%methanol-chloroform and triturated in ethyl acetate to give white powder(460 mg, 68%), m.p. 235°-236° C. dec.; ¹ H-NMR(DMSO-d₆)δ: 8.38 and 7.97(both s, 1 each, 2 benzimidazole CH), 5.75-5.65 (m, 1, OCH), 5.2-5.0 (m,2, OCH and NCH), 2.11 (s) overlapped by 2.2-2.05 (m, total 6, OAc withCH₂ and CH), 1.95 (s, 3, OAc), 1.22 (d, J=6.3 Hz, 3, CHCH₃); massspectrum (CI): 463 (M+1).

Part E. (±)-(1R*, 2S*, 3R*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-methyl-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3R*,5S*)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-methyl-1,2-cyclopentanediyldiacetate (Part D, 350 mg, 0.75 mmole) and cyclopropylamine (Aldrich,0.53 mL) were refluxed in methoxyethanol (5 mL) for 5 hours. 1N sodiumhydroxide (0.75 mL) was added to the cooled reaction mixture andvolatiles were evaporated in vacuo. The residue was chromatographed onsilica gel. Product was eluted with 5% methanol-chloroform.Recrystallization from methanol-ethyl acetate gave (±)-(1R*, 2S*, 3R*,5S*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-methyl-1,2-cyclopentanediolas white crystals (170 mg, 64%); m.p. 231°-233° C.; ¹ H-NMR(DMSO-d₆)δ:7.48 and 7.39 (both s, 1 each, 2 benzimidazole CH), 7.10 (m, 1, NH),4.83 (d, J=5.9 Hz, 1, OH), 4.74 (d, J=5.1 Hz, 1, OH), 4.5-4.3 (m, 2, NCHand OCH), 3.7-3.6 (m, 1, OCH), 2.85-2.7 (m, 1, CHNH), 2.1-1.8 (m, 2, CH₂and CH), 1.7-1.5 (m, 1, CH), 1.16 (d, J=5.4 Hz, 3, CHCH₃), 0.8-0.5 (m,4, 2 CH₂ of cyclopropyl); mass spectrum (CI): 356 (M+1).

Anal. Calcd. for C₁₆ H₁₉ N₃ Cl₂ O₂ : C, 53.95; H, 5.38; N, 11.80; Cl,19.90. Found: C, 53.75; H, 5.45; N, 11.71; Cl, 19.98.

Example 82 (1R, 2S, 3S, 5S)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanedio

A solution of (1R, 2S, 3S,5S)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol(500 mg, 1.26 mmole) was stirred in tert-butylamine (Aldrich, 98%, 20mL) in a Parr bomb maintained at 148° C. (oil bath) for 48 hours. Thebomb was cooled and the resulting pale yellow solution diluted withethanol containing 1N sodium hydroxide (1.2 mL). Volatiles wereevaporated in vacuo and the residue was chromatographed on silica gel.Title compound was eluted with 10% methanol-chloroform as a colorlessoil. The oil was dissolved in absolute ethanol, concentrated to an oil,and triturated with water (3 mL) to give (1R, 2S, 3S,5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediolas white powder (303 mg, 61%), m.p.: collapses to glass at 116°-150° C.;¹ H-NMR(DMSO-d₆)δ: 7.63 and 7.43 (both s, 2, aromatic CH), 6.15 (s, 1,NH), 5.08 (t, J=4.3 Hz, 1, OH), 4.85 (d, J=7.4 Hz, 1, OH), 4.71 (d,J=3.8 Hz, 1, OH), 4.7-4.5 (m, 1, NCH), 4.45-4.3 (m, 1, OCH), 3.80 (m, 1,OCH), 3.7-3.4 (m, 2, OCH₂), 2.2-1.85 (m, 3, CH₂ and CH of cyclopentane),1.47 (s, 9, 3 CH₃); mass spectrum (CI): 388(M+1); [α]²⁰ ₅₈₉ -4.0°, [α]²⁰₅₇₈ -4.3°, [α]²⁰ ₅₄₆ -6.0°, [α]²⁰ ₄₃₆ -22.6°, [α]²⁰ ₃₆₅ -82.1° (c=0.420,methanol).

Anal. Calcd. for C₁₇ H₂₃ N₃ Cl₂ O₃.0.40 H₂ O: C, 51.63; H, 6.07; N,10.62; Cl, 17.93. Found: C, 51.50; H, 5.99; N, 10.54; Cl, 17.96.

Example 83 (±)-(1R*, 2S*, 3S*,5S*)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

A solution of (±)-(1R*, 2S*, 3S*,5S*)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol(750 mg, 1.44 mmole) was stirred in tert-butylamine (Aldrich, 98%, 25mL) in a Parr bomb maintained at 90° C. (oil bath) for 6 days. Volatileswere evaporated in vacuo and the residual solids refluxed in ethanol (30mL) with aqueous dimethylamine (Aldrich, 40%, 2 mL) for one hour.Volatiles were evaporated and the residual solids chromatographed onsilica gel. Elution with 10% methanol-ethyl acetate gave title compoundas colorless glass. Solidification from water gave (±)-(1R*, 2S*, 3S*,5S*)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediolas a white powder (150 mg, 26%); m.p. 130°-132° C.; ¹ H-NMR(DMSO-d₆)identical with that of the enatiomer described in Example 82.

Anal. Calcd. for C₁₇ H₂₃ N₃ Cl₂ O₃.0.65 H₂ O.0.07 C₂ H₅ OH: C, 51.18: H,5.94; N, 10.47; Cl, 17.63. Found: C, 51.34; H, 6.06; N, 10.37; Cl,17.58.

Example 84 (±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R*, 2S*, 3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyldiacetate (750 mg, 1.44 mmole) was refluxed in ethanol (10 mL) withisopropylamine (1.22 mL, Aldrich) under nitrogen for 18 hours. A secondportion of isopropylamine (1.22 mL) was added and reflux continued foran additional 24 hours. Volatiles were evaporated, the residue wasredissolved in ethanol, 1N sodium hydroxide (1.44 mL) was added, andvolatiles were reevaporated. The residue was chromatographed on a silicagel column. Title compound was eluted with 10% methanol-chloroform as acolorless glass. The glass was crystallized from ethyl acetate-hexanesto give (±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediolas white crystals (305 mg, 57%); m.p. 213°-214° C.; ¹ H-NMR(DMSO-d₆)identical with that of the enantiomer described in Example 75.

Anal. Calcd. for C₁₆ H₂₁ N₃ Cl₂ O₃ : C, 51.35; H, 5.66; N, 11.23; Cl,18.95. Found: C, 51.27; H, 5.69; N, 11.17; Cl, 18.88.

We claim:
 1. Compounds of formulae (I) and (I-1) ##STR7## wherein R¹ isH, CH₃ or CH₂ OH; R² is H or OH; R³ is H or OH; or R² and R³ togetherform a bond:R⁴ is H, Cl, Br, I, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₁₋₄ perfluoroalkyl, NH₂, C₁₋₄ alkylamino, C₁₋₄dialkylamino, C₃₋₇ cycloalkylamino, diC₃₋₇ cycloalkylamino, N-C₁₋₄alkyl-N-C₃₋₇ cycloalkylamino, N-C₁₋₄ alkyl-N-C₃₋₇ cycloalkylC₁₋₄alkylamino, diC₃₋₇ cycloalkylC₁₋₄ alkylamino, C₃₋₇ cycloalkylC₁₋₄alkylamino, N-C₃₋₇ cycloalkyl-N-C₃₋₇ cycloalkylC₁₋₄ alkylamino, SH, C₁₋₄alkylthio, C₆₋₁₀ arylC₁₋₄ alkylthio, OH, C₁₋₄ alkoxy, C₆₋₁₀ arylC₁₋₄alkoxy or C₆₋₁₀ arylC₁₋₄ alkyl; and R⁵, R⁶ and R⁷ are independentlyselected from H, F, Cl, Br, I, CF₃ and CH₃, provided that at least oneof R¹, R² and R³ is or contains OH; and pharmaceutically acceptablesalts thereof.
 2. Compounds as claimed in claim 1 in which R⁴ is CH₃,C₁₋₄ alkylamino, C₃₋₇ cycloalkylamino, Cl or Br; R⁵ is H; and R⁶ and R⁷are each Cl.
 3. A compound according to claim 1 or 2 which is (1R, 2S,3S,5S)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanedioland pharmaceutically acceptable salts thereof.
 4. A compound accordingto claim 1 which is selected from(±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1R, 2S, 3S,5S)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;or (±)-(1R*, 2S*, 3S*,5S*)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;andpharmaceutically acceptable salts thereof.
 5. A method for the treatmentof a herpes viral infection in a subject which comprises treating thesubject with a therapeutically effective amount of at least one compoundof formula (I) or (I-1), as defined in claim 1, or a pharmaceuticallyacceptable salts thereof.
 6. A method according to claim 5 wherein theherpes viral infection is a cytomegalovirus infection.
 7. A methodaccording to claims 5 or 6 wherein said compound of formula (I) or (I1)is selected from(±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1 R, 2S, 3S,5S)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;or (±)-(1R*, 2S*, 3S*,5S*)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;andpharmaceutically acceptable salts thereof.
 8. Pharmaceuticalformulations comprising at least one compound of formula (I) or (I-1),as defined in claim 1, or a pharmaceutically acceptable salts thereoftogether with at least one pharmaceutically acceptable carrier orexcipient.
 9. A pharmaceutical formulation according to claim 8 whereinsaid compound of formula (I) or (I1) is selected from(±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(±)-(1R*, 2S*, 3S*,5S*)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1R, 2S, 3S,5S)-5-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;(1R, 2S, 3S,5S)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;or (±)-(1R*, 2S*, 3S*,5S*)-5-[2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;andpharmaceutically acceptable salts thereof.